Exploring the Antimicrobial Resistance Profile of Salmonella typhi and Its Clinical Burden.

Background: Typhoid fever caused by Salmonella enterica serovar Typhi (S. typhi) continues to pose a significant risk to public health in developing countries, including Pakistan. This study investigated the epidemiological factors linked to suspected and confirmed S. typhi infections in Peshawar's hospital population. Methodology: A total of 5735 blood samples of patients with suspected enteric fever were collected from September 2022 to November 2023. S. typhi infection was confirmed using microbiological culture of blood samples, biochemical-based tests, and DNA-sequencing methods. Drug sensitivity testing on cultures was conducted as per the CLSI guidelines. Chi-square tests were used to analyze the clinical and epidemiologic characteristics of 5735 samples stratified by S. typhi infection status, and risk factors were assessed by applying logistic regression models to estimate odds ratios (ORs). Results: The number of confirmed typhoid fever cases in this hospital-based study population was 691 (/5735, 12.0%), more prevalent in males (447/3235 13.8%) and children (0-11 years) (429/2747, 15.6%). Compared to children, the risk of S. typhi infection was lower in adolescence (adjusted OR = 0.52; 95% CI: 0.42-0.66), adulthood (19-59 years; aOR = 0.30; 95% CI: 0.25-0.38), and older adulthood (aOR = 0.08; 95% CI: 0.04-0.18) (p < 0.001). Compared to males, the risk of S. typhi infection was lower in females (aOR = 0.67; 95% CI = 0.56-0.80; p = 0.002). Living in a rural residence (compared to urban) was associated with a higher risk of infection (aOR = 1.38; 95% CI: 1.16-1.63; p = 0.001), while access to a groundwater source (compared to municipal water supply) led to a lower risk (aOR = 0.56; 95% CI: 0.43-0.73; p = 0.002). Vaccination demonstrated a robust protective effect (aOR = 0.069; 95% CI = 0.04-0.11, p = 0.002). For those with typhoid infections, clinical biomarker analysis revealed the presence of leucopenia (65/691, 9.4%), thrombocytopenia (130/691, 18.8%), and elevated alanine aminotransferase (ALT) (402/691, 58.2%) and C-reactive protein (CRP) (690/691, 99.9%) levels. Worryingly, among the positive S. typhi isolates, there was a high prevalence of drug resistance (653/691), including multidrug-resistant (MDR 82/691, 11.9%) and extensively drug-resistant types (XDR, 571/691, 82.6%). Conclusions: This study highlights the importance of age, sex, locality, water source, and vaccination status in shaping the epidemiological landscape of S. typhi in the Peshawar district. It implies that expanding vaccination coverage to the broader population of Khyber Pakhtunkhwa province, particularly in the district of Peshawar, would be beneficial.

Video domain adaptation for semantic segmentation using perceptual consistency matching.

Unsupervised domain adaptation (UDA) aims to transfer knowledge in previous and related labeled datasets (sources) to a new unlabeled dataset (target). Despite the impressive performance, existing approaches have largely focused on image-based UDA only, and video-based UDA has been relatively understudied and received less attention due to the difficulty of adapting diverse modal video features and modeling temporal associations efficiently. To address this, existing studies use optical flow to capture motion cues between in-domain consecutive frames, but is limited by heavy compute requirements and modeling flow patterns across diverse domains is equally challenging. In this work, we propose an adversarial domain adaptation approach for video semantic segmentation that aims to align temporally associated pixels in successive source and target domain frames without relying on optical flow. Specifically, we introduce a Perceptual Consistency Matching (PCM) strategy that leverages perceptual similarity to identify pixels with high correlation across consecutive frames, and infer that such pixels should correspond to the same class. Therefore, we can enhance prediction accuracy for video-UDA by enforcing consistency not only between in-domain frames, but across domains using PCM objectives during model training. Extensive experiments on public datasets show the benefit of our approach over existing state-of-the-art UDA methods. Our approach not only addresses a crucial task in video domain adaptation but also offers notable improvements in performance with faster inference times.

Ultrasound-Activated PROTAC Prodrugs Overcome Immunosuppression to Actuate Efficient Deep-Tissue Sono-Immunotherapy in Orthotopic Pancreatic Tumor Mouse Models.

The degradation of oncoproteins mediated by proteolysis-targeting chimera (PROTAC) has emerged as a potent strategy in cancer therapy. However, the clinical application of PROTACs is hampered by challenges such as poor water solubility and off-target adverse effects. Herein, we present an ultrasound (US)-activatable PROTAC prodrug termed NPCe6+PRO for actuating efficient sono-immunotherapy in a spatiotemporally controllable manner. Specifically, US irradiation, which exhibits deep-tissue penetration capability, results in Ce6-mediated generation of ROS, facilitating sonodynamic therapy (SDT) and inducing immunogenic cell death (ICD). Simultaneously, the generated ROS cleaves the thioketal (TK) linker through a ROS-responsive mechanism, realizing the on-demand activation of the PROTAC prodrug in deep tissues. This prodrug activation results in the degradation of the target protein BRD4, while simultaneously reversing the upregulation of PD-L1 expression associated with the SDT process. In the orthotopic mouse model of pancreatic tumors, NPCe6+PRO effectively suppressed tumor growth in conjunction with US stimulation.

Stabilizing Lead Halide Perovskites via an Organometallic Chemical Bridge for Efficient and Stable Photovoltaics.

Defects around the surface and grain boundaries of perovskite films normally cause severe nonradiative recombination and imbalanced charge carrier transport, further limiting both the efficiency and stability of perovskite solar cells (PSCs). To tackle this critical issue, we propose a chemical bridge strategy to reconstruct the interface using organometallic molecules. The commercially available molecule bis(diphenylphosphino)ferrocene (FcP2), with a unique bridge molecular structure, anchors and chelates Pb atoms by forming strong Pb-P bonds and further passivates both surfaces and grain boundaries. Detailed characterization revealed that bridge molecule FcP2 reconstruction can effectively suppress nonradiative recombination, and the electron delocalization properties of the ferrocene core can further achieve more balanced interfacial carrier transport. The resultant N-i-P PSC device outputs close to 25% efficiency together with one of the best reported operational stabilities, maintaining over 95% of the initial efficiency after 1000 h of continuous operation at the maximum power point under 1-sun illumination.

6-Methoxyflavone antagonizes chronic constriction injury and diabetes associated neuropathic nociception expression.

Neuropathy is a disturbance of function or a pathological change in nerves causing poor health and quality of life. A proportion of chronic pain patients in the community suffer persistent neuropathic pain symptoms because current drug therapies may be suboptimal so there is a need for new therapeutic modalities. This study investigated the neuroprotective flavonoid, 6-methoxyflavone (6MF), as a potential therapeutic agent and gabapentin as the standard comparator, against neuropathic models. Thus, neuropathic-like states were induced in Sprague-Dawley rats using sciatic nerve chronic constriction injury (CCI) mononeuropathy and systemic administration of streptozotocin (STZ) to induce polyneuropathy. Subsequent behaviors reflecting allodynia, hyperalgesia, and vulvodynia were assessed and any possible motoric side-effects were evaluated including locomotor activity, as well as rotarod discoordination and gait disruption. 6MF (25-75 mg/kg) antagonized neuropathic-like nociceptive behaviors including static- (pressure) and dynamic- (light brushing) hindpaw allodynia plus heat/cold and pressure hyperalgesia in the CCI and STZ models. 6MF also reduced static and dynamic components of vulvodynia in the STZ induced polyneuropathy model. Additionally, 6MF reversed CCI and STZ suppression of locomotor activity and rotarod discoordination, suggesting a beneficial activity on motor side effects, in contrast to gabapentin. Hence, 6MF possesses anti-neuropathic-like activity not only against different nociceptive modalities but also impairment of motoric side effects.

Self-assembled metal-phenolic network nanoparticles for delivery of a cisplatin prodrug for synergistic chemo-immunotherapy.

Despite cisplatin's pivotal role in clinically proven anticancer drugs, its application has been hampered by severe side effects and a grim prognosis. Herein, we devised a glutathione (GSH)-responsive nanoparticle (PFS-NP) that integrates a disulfide bond-based amphiphilic polyphenol (PP-SS-DA), a dopamine-modified cisplatin prodrug (Pt-OH) and iron ions (Fe3+) through coordination reactions between Fe3+ and phenols. After entering cells, the responsively released Pt-OH and disulfide bonds eliminate the intracellular GSH, in turn disrupting the redox homeostasis. Meanwhile, the activated cisplatin elevates the intracellular H2O2 level through cascade reactions. This is further utilized to produce highly toxic hydroxyl radicals (˙OH) catalyzed by the Fe3+-based Fenton reaction. Thus, the amplified oxidative stress leads to immunogenic cell death (ICD), promoting the maturation of dendritic cells (DCs) and ultimately activating the anti-tumor immune system. This innovative cisplatin prodrug nanoparticle approach offers a promising reference for minimizing side effects and optimizing the therapeutic effects of cisplatin-based drugs.

Tumor Acidity-Triggered Bioorthogonal Reactions for Biomedical Applications.

Cancer is one of the most serious threats to human health. Over the past few years, researchers have incrementally uncovered the pivotal role of tumor acidity in tumor formation, development, and treatment. In addition, bioorthogonal reactions have been widely used in tumor diagnosis and therapy, owing to their advantageous characteristics, including small ligand size, biocompatibility, fast reaction kinetics, and high chemospecificity. Consequently, bioorthogonal reactions triggered by tumor acidity have become an emerging strategy in biomedical applications. On this basis, we first elucidate the concept and major strategies of tumor acidity-triggered bioorthogonal reactions. Additionally, we review the progress in biomedical applications, with a particular focus on their importance in disease diagnosis and treatment. Finally, clinical challenges and future trends are also outlooked.

Exploring the Therapeutic Potential of Petiveria alliacea L. Phytochemicals: A Computational Study on Inhibiting SARS-CoV-2's Main Protease (Mpro).

The outbreak of SARS-CoV-2, also known as the COVID-19 pandemic, is still a critical risk factor for both human life and the global economy. Although, several promising therapies have been introduced in the literature to inhibit SARS-CoV-2, most of them are synthetic drugs that may have some adverse effects on the human body. Therefore, the main objective of this study was to carry out an in-silico investigation into the medicinal properties of Petiveria alliacea L. (P. alliacea L.)-mediated phytocompounds for the treatment of SARS-CoV-2 infections since phytochemicals have fewer adverse effects compared to synthetic drugs. To explore potential phytocompounds from P. alliacea L. as candidate drug molecules, we selected the infection-causing main protease (Mpro) of SARS-CoV-2 as the receptor protein. The molecular docking analysis of these receptor proteins with the different phytocompounds of P. alliacea L. was performed using AutoDock Vina. Then, we selected the three top-ranked phytocompounds (myricitrin, engeletin, and astilbin) as the candidate drug molecules based on their highest binding affinity scores of -8.9, -8.7 and -8.3 (Kcal/mol), respectively. Then, a 100 ns molecular dynamics (MD) simulation study was performed for their complexes with Mpro using YASARA software, computed RMSD, RMSF, PCA, DCCM, MM/PBSA, and free energy landscape (FEL), and found their almost stable binding performance. In addition, biological activity, ADME/T, DFT, and drug-likeness analyses exhibited the suitable pharmacokinetics properties of the selected phytocompounds. Therefore, the results of this study might be a useful resource for formulating a safe treatment plan for SARS-CoV-2 infections after experimental validation in wet-lab and clinical trials.

Development of silver-doped copper oxide and chitosan nanocomposites for enhanced antimicrobial activities.

Antimicrobial resistance (AMR) has emerged as a significant and pressing public health concern, posing serious challenges to effectively preventing and treating persistent diseases. Despite various efforts made in recent years to address this problem, the global trends of AMR continue to escalate without any indication of decline. As AMR is well-known for antibiotics, developing new materials such as metal containing compounds with different mechanisms of action is crucial to effectively address this challenge. Copper, silver, and chitosan in various forms have demonstrated significant biological activities and hold promise for applications in medicine and biotechnology. Exploring the biological properties of these nanoparticles is essential for innovative therapeutic approaches in treating bacterial and fungal infections, cancer, and other diseases. To this end, the present study aimed to synthesize silver@copper oxide (Ag@CuO) nanoparticles and its chitosan nanocomposite (Chi-Ag@CuO) to investigate their antimicrobial efficacy. Various established spectroscopic and microscopic methods were employed for characterization purposes, encompassing scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). Subsequently, the antimicrobial activity of the nanoparticles was assessed through MIC (minimum inhibitory concentration), MBC (minimum bactericidal concentration), and well-disk diffusion assays against Pseudomonas aeruginosa, Acinetobacter baumannii Staphylococcus aureus, Staphylococcus epidermidis, and Candida albicans. The size of the CuO-NPs, Ag@CuO, and Chi-Ag@CuO NPs was found to be 70-120 nm with a spherical shape and an almost uniform distribution. The nanocomposites were found to possess a minimum inhibitory concentration (MIC) of 5 µg/mL and a minimum bactericidal concentration (MBC) of 250 µg/mL. Moreover, these nanocomposites generated varying clear inhibition zones, with diameters ranging from a minimum of 9 ± 0.5 mm to a maximum of 25 ± 0.5 mm. Consequently, it is evident that the amalgamation of copper-silver-chitosan nanoparticles has exhibited noteworthy antimicrobial properties in the controlled laboratory environment, surpassing the performance of other types of nanoparticles.

A Synergistic Chemoimmunotherapy System Leveraging PD-L1 Blocking and Bioorthogonal Prodrug Activation.

Novel strategies to facilitate tumor-specific drug delivery and restore immune attacks remain challenging in overcoming the current limitations of chemoimmunotherapy. An antitumor chemoimmunotherapy system comprising bioorthogonal reaction-ready group tetrazine (TZ) modified with an anti-PD-L1 antibody (αPD-L1TZ) and TZ-activatable prodrug vinyl ether-doxorubicin (DOX-VE) for self-reinforced anti-tumor chemoimmunotherapy is proposed. The αPD-L1TZ effectively disrupts the PD-L1/PD-1 interaction and activates the DOX prodrug in situ through the bioorthogonal click reaction of TZ and VE. Conversely, the activated DOX upregulates PD-L1 on the surface of tumor cells, facilitating tumor accumulation of αPD-L1TZ and enhancing DOX-VE activation. Furthermore, the activated DOX-induced immunogenic cell death of tumor cells, substantially improving the response efficiency of αPD-L1 in an immune-suppressive tumor microenvironment. Thus, PD-L1 blocking and bioorthogonal in situ prodrug activation synergistically enhance the antitumor efficacy of the chemoimmunotherapy system. Therefore, the system significantly enhances αPD-L1 tumor accumulation and prodrug activation and induces a robust immunological memory effect to prevent tumor recurrence and metastasis. Thus, a feasible chemoimmunotherapy combination regimen is presented.

First Report of Wilt Caused by Fusarium nanum (FIESC 25) on Mungbean (Vigna radiata) in Pakistan.

Mungbean, Vigna radia (L.) R. Wilczek, is ranked 2nd next to chickpea (Cicer arietinum) in total cultivation and production in Pakistan. In August of 2022 and 2023, mungbean plants (cv. PRI Mung-2018) were found wilting in a field at the Ayub Agricultural Research Institute, Faisalabad, Pakistan. Wilted leaves turned yellow, died, but remained attached to the stem. Vascular tissue at the base of the stem showed light to dark brown discoloration. Roots were stunted with purplish brown to black discoloration. Symptomatic mungbean plants were collected from fields at five different locations (20 samples/location). Disease incidence was similar among the five fields, ranging from 5 to 10% at each location depending upon type of germplasm and date of sowing. For fungal isolation and morphological identification, symptomatic stem and root tissues were cut into ~5 mm2 pieces with a sterilized blade. Tissues were surface-sterilized for one min in a 0.5% sodium hypochlorite solution, rinsed twice in sterilized water, air dried on sterilized filter paper, and aseptically placed on potato dextrose agar (PDA) containing 0.5 g/L-1 streptomycin sulphate. Plates were incubated for 3-4 days at 25 ± 2°C with a 12-h photoperiod. Single-spore cultures were used for morphological and molecular analyses. Isolates on PDA grew rapidly and produced abundant white aerial mycelium that turned off-white to beige with age. Macroconidia were hyaline, falcate, typically 3-to-6 septate with a pointed apical cell and a foot-shaped basal cell, measuring 24.5-49.5 x 2.7-4.7 µm (n = 40). Globose to obovate chlamydospores measuring 5.8 ± 0.5 µm (n = 40) were produced singly or in chains and were intercalary or terminal and possessed roughened walls. The morphological data indicated the isolates were members of the genus Fusarium (Leslie and Summerell 2006). To obtain a species-level identification, a portion of translation elongation factor 1-α (TEF1), the largest subunit of RNA polymerase (RPB1), and the second largest subunit of RNA polymerase (RPB2) region were PCR amplified and sequenced using EF1/EF2 (O'Donnell et al. 1998), Fa/G2R (Hofstetter et al. 2007), and 5f2/7cr (Liu et al. 1999) primers, respectively. DNA sequences of these genes were deposited in GenBank under accession numbers MW059021, MW059017 and MW059019, respectively. The partial TEF1, RPB1 and RPB2 sequences were queried against the Fusarium MLST database (https://fusarium.mycobank.org/page/Fusarium_identification), using the polyphasic identification tool. The BLASTn search revealed 99.9% identity of the isolate to F. nanum (Xia et al. 2019), formerly FIESC 25 of the F. incarnatum-equiseti species complex (MRC 2610, NRRL 54143; O'Donnell et al. 2018). To confirm pathogenicity, roots of 3-5 leaf stage mungbean seedlings were soaked in a 106 spores ml-1 conidial suspension of the fungus for 15 min and then planted in 10 cm pots containing sterilized soil. Mock-inoculated plants with sterile water served as a negative control. Twenty pots that were used for each inoculated and control treatment were maintained at 25 ± 2°C, 14:8 h photoperiod, and 80% relative humidity in a growth chamber. After 15 days, leaf yellowing, internal browning from the base of stems and root discoloration was observed in all the inoculated plants. The uninoculated negative control plants remained asymptomatic. Fusarium nanum was re-isolated from artificially inoculated plants and identified by colony growth, conidial characteristics on PDA and molecular analyses (TEF1). To our knowledge, this is the first report of wilt caused by F.nanum on mungbean in Pakistan. In Pakistan, mungbean cultivation in irrigated areas has increased in recent years. It has been introduced frequently in citrus orchards, crop rotation of maize and sesame, intercropping with sugarcane and as green manure. However, citrus, maize, sesame and sugarcane are also hosts of Fusarium spp. Therefore, this information warrants sustainable crop protection and may have an impact on further interaction of F. nanum with other wilt pathogens.

Revision Lumbar Spine Surgeries: An Early Career Neurosurgery Experience.

BACKGROUND: The aims and ambitions of a surgeon in the early years of his professional career are to make a good reputation by providing excellent patient outcomes and avoiding complex and difficult surgeries. Revision lumbar spine surgeries (RLSSs) pose a significant challenge in terms of surgical management, as the moribund anatomy increases the risk of complications, adding to an unlikely outcome. OBJECTIVE: We conducted this study to determine the clinical indications and outcomes of RLSSs performed by an early career neurosurgeon. MATERIALS AND METHODS: This cross-sectional study was conducted after approval from the hospital's ethical committee, and data was collected in late December of 2022 and early January 2023, from retrospective records for a single early career neurosurgeon. A form was filled with each patient's data, such as age, gender, time since surgery, indication for surgery, operative findings, types of surgery performed, etc. All variables were noted for the patient and were further categorized, based on the clinical records, into many sub-categories. RESULTS: Almost 400 lumbar spine surgeries were performed by the surgeon, and about 45 (11.25%) were revision surgeries, and the full record was available for 42 surgeries. These patients' ages ranged from 22 to 70 years, and the mean age was about 46.74±13.29 SD. The common symptoms leading to revision surgeries were numbness and pain in 17 (40.5%) patients each; common per-operative findings were recurrent disc in eight patients (19%), infection in nine patients (21.4%), and fibrosis/adhesions in 16 (38.1%); most common surgeries performed were diskectomy in 11 (26.2%) and diskectomy plus release of adhesions in 12 (28.6%); complications occurred in 14 (33%), and good to excellent outcomes was recorded in 29 (69%) cases.  Conclusion: RLSSs are difficult compared to first-time lumbar spine surgeries, and the moribund anatomy predisposes to complications, and better shall be dealt with great care and, at the minimum, shall be embarked upon as a team.

Phytoremediation of Arsenic (As) in rice plants, mediated by Bacillus subtilis strain IU31 through antioxidant responses and phytohormones synthesis.

Bacteria-assisted phytoremediation uses bacteria to promote plant health and improve its ability to remediate toxic heavy metals like Arsenic (As). Here, we isolated rhizobacteria and identified them as Bacillus subtilis strain IU31 using 16S rDNA sequencing. IU31 showed phosphate solubilization potential on Pikovskaya agar medium and produced siderophores, which were detected on Chromium Azurol-S (CAS) agar medium. Indole-3-acetic acid (IAA) and gibberellins (GAs), namely GA1, GA3, GA4, GA7, GA9, GA12, GA15, and GA24, were quantified by GC/MS-SIM analysis. The expression levels of genes involved in GA and IAA biosynthesis, such as cyp112, cyp114, trpA, and trpB, were assessed using semi-quantitative RT-PCR. Plant bioassays showed that As at a 15 mg/kg concentration reduced plant growth, chlorophyll content, and biomass. However, IU31 inoculation significantly improved plant growth dynamics, enhancing As accumulation by up to 50% compared with uninoculated plants. IU31 inoculation induced the bioconcentration factor (BCF) and bioaccumulation factor (BAF) of As in plants compared to uninoculated plants, but the translocation factor (TF) of As was unaffected by IU31 inoculation. IU31 inoculation effectively restored glutathione-S-transferase (GST) and catalase (CAT) enzyme activities, as well as glutathione (GSH) and hydrogen peroxide concentrations to nearly normal levels, which were significantly elevated in plants exposed to As stress. These results show that IU31 improves plant health and growth by producing IAA and GAs, which might contribute to the uptake and detoxification of As.

Prevalence of crimean Congo hemorrhagic fever in Khyber Pakhtunkhwa, Pakistan.

BACKGROUND: CCHFV is well recognized as a major public health threat and its prevalence and epidemiological distribution in Pakistan and specifically in KP province is not well documented. METHODS: We used a gold-standard PCR-based diagnostic assay for confirmation of CCHFV among suspected patients. A total of 150 patients were enrolled from June 2022 to September 2022 and their blood samples were collected for PCR confirmation. RESULTS: The overall positivity rate for CCHFV was 26.67 %, with the virus mostly prevalent in the middle-aged group (21-40 years). In the July of 2022, a significant spike in the prevalence of CCHFV was observed in provincial capital Peshawar with the highest burden (31.57 %). CONCLUSION: Our findings indicate the necessity of strengthening CCHFV monitoring programs and intensifying efforts to identify hotspot regions for effective surveillance and control of CCHFV. The months before the Eid-ul-Adha are crucial in the context of CCHFV control.

Stable Isotope Analyses Reveal Impact of Fe and Zn on Cd Uptake and Translocation by Theobroma cacao.

High concentrations of toxic cadmium (Cd) in soils are problematic as the element accumulates in food crops such as rice and cacao. A mitigation strategy to minimise Cd accumulation is to enhance the competitive uptake of plant-essential metals. Theobroma cacao seedlings were grown hydroponically with added Cd. Eight different treatments were used, which included/excluded hydroponic or foliar zinc (Zn) and/or iron (Fe) for the final growth period. Analyses of Cd concentrations and natural stable isotope compositions by multiple collector ICP-MS were conducted. Cadmium uptake and translocation decreased when Fe was removed from the hydroponic solutions, while the application of foliar Zn-EDTA may enhance Cd translocation. No significant differences in isotope fractionation during uptake were found between treatments. Data from all treatments fit a single Cd isotope fractionation model associated with sequestration (seq) of isotopically light Cd in roots and unidirectional mobilisation (mob) of isotopically heavier Cd to the leaves (ε114Cdseq-mob = -0.13‱). This result is in excellent agreement with data from an investigation of 19 genetically diverse cacao clones. The different Cd dynamics exhibited by the clones and seen in response to different Fe availability may be linked to similar physiological processes, such as the regulation of specific transporter proteins.

Does renal denervation require cardiovascular outcome-driven data?

Hypertension is a major driver of cardiovascular disease with a prevalence of 32-34% in adults worldwide. This poses a formidable unmet challenge for healthcare systems, highlighting the need for enhanced treatment strategies. Since 2017, eight major sham-controlled randomised controlled trials have examined the effectiveness and safety of renal denervation (RDN) as therapy for BP control. Although most trials demonstrated a reduction in systolic 24-hour/daytime ambulatory BP compared to control groups, open to discussion is whether major adverse cardiovascular events (MACE)-driven RDN trials are necessary or whether the proof of BP reduction as a surrogate for better cardiovascular outcomes is sufficient. We conducted an analysis of the statistical methods used in various trials to assess endpoint definitions and determine the necessity for MACE-driven outcome data. Such comprehensive analysis provides further evidence to confidently conclude that RDN significantly reduces blood pressure compared to sham controls. Importantly, this enables the interpolation of RDN trial endpoints with other studies that report on outcome data, such as pharmacological trials which demonstrate a significant reduction in MACE risk with a decrease in BP. Moreover, limitations associated with directly evaluating outcome data further support the use of BP as a surrogate endpoint. For example, conducting lengthier trials with larger numbers of participants to ensure robust statistical power presents a substantial challenge to evaluating outcome data. Thus, in light of the crucial need to tackle hypertension, there are notable advantages of considering BP as a surrogate for outcome data.

Beneficial Effects of Natural Alkaloids from Berberis glaucocarpa as Antidiabetic Agents: An In Vitro, In Silico, and In Vivo Approach.

Diabetes, also known as diabetes mellitus (DM), is a metabolic disorder characterized by an abnormal rise in blood sugar (glucose) levels brought on by a complete or partial lack of insulin secretion along with corresponding changes in the metabolism of lipids, proteins, and carbohydrates. It has been reported that medicinal plants play a pivotal role in the treatment of various ailments such as diabetes mellitus, dyslipidemia, and hypertension. The current study involved exploring the acute toxicity and in vivo antidiabetic activity of berberine (WA1), palmatine (WA2), and 8-trichloromethyl dihydroberberine (WA3) previously isolated from Berberis glaucocarpa Stapf using a streptozotocin (STZ)-induced diabetic rat model. Body weight and blood glucose level were assessed on a day interval for 4 weeks. Biochemical parameters, antioxidant enzymes, and oxidative stress markers were also determined. In an acute toxicity profile, the WA1, WA2, and WA3 were determined to be nontoxic up to 500 mg/kg (b.w). After the second and third weeks of treatment (14 and 21 days), the blood glucose levels in the WA1-, WA2-, and WA3-treated groups were significantly lower than those in the diabetic control group (476.81 ± 8.65 mg/dL, n = 8, P < 0.001). On the 21st day, there was a decrease in the blood glucose level and the results obtained were 176.33 ± 4.69, 197.21 ± 4.80, and 161.99 ± 4.75 mg/dL (n = 8, P < 0.001) for WA1, WA2, and WA3 at 12 mg/kg, respectively, as opposed to the diabetic control group (482.87 ± 7.11 mg/dL, n = 8, P < 0.001). Upon comparison with the diabetic group at the end of the study (28 days), a substantial drop in the glucose level of WA3 at 12 mg/kg (110.56 ± 4.11 mg/dL, n = 8, P < 0.001) was observed that was almost near the values of the normal control group. The treated groups (WA1, WA2, and WA3) treated with the samples displayed a significant decline in the levels of HbA1c. Treatment of the samples dramatically lowered the lipid level profile. In groups treated with samples, plasma levels of triglycerides, total cholesterol, and LDL were significantly lowered [F (5, 42) = 100.6, n = 8, P < 0.001]; these levels were also significantly decreased [F (5, 42) = 129.6 and 91.17, n = 8, P < 0.001]. In contrast to the diabetes group, all treated groups had significantly higher HDL levels [F (5, 42) = 15.46, n = 8, P < 0.001]. As a result, hypolipidemic activity was anticipated in the samples. In addition to that, the activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) was considerably elevated in the groups treated with the sample compared to the diabetic control group (n = 8, P < 0.001).

Explaining decisions of a light-weight deep neural network for real-time coronary artery disease classification in magnetic resonance imaging.

In certain healthcare settings, such as emergency or critical care units, where quick and accurate real-time analysis and decision-making are required, the healthcare system can leverage the power of artificial intelligence (AI) models to support decision-making and prevent complications. This paper investigates the optimization of healthcare AI models based on time complexity, hyper-parameter tuning, and XAI for a classification task. The paper highlights the significance of a lightweight convolutional neural network (CNN) for analysing and classifying Magnetic Resonance Imaging (MRI) in real-time and is compared with CNN-RandomForest (CNN-RF). The role of hyper-parameter is also examined in finding optimal configurations that enhance the model's performance while efficiently utilizing the limited computational resources. Finally, the benefits of incorporating the XAI technique (e.g. GradCAM and Layer-wise Relevance Propagation) in providing transparency and interpretable explanations of AI model predictions, fostering trust, and error/bias detection are explored. Our inference time on a MacBook laptop for 323 test images of size 100x100 is only 2.6 sec, which is merely 8 milliseconds per image while providing comparable classification accuracy with the ensemble model of CNN-RF classifiers. Using the proposed model, clinicians/cardiologists can achieve accurate and reliable results while ensuring patients' safety and answering questions imposed by the General Data Protection Regulation (GDPR). The proposed investigative study will advance the understanding and acceptance of AI systems in connected healthcare settings.

Peeling off the layers from microbial dark matter (MDM): recent advances, future challenges, and opportunities.

Microbes represent the most common organisms on Earth; however, less than 2% of microbial species in the environment can undergo cultivation for study under laboratory conditions, and the rest of the enigmatic, microbial world remains mysterious, constituting a kind of "microbial dark matter" (MDM). In the last two decades, remarkable progress has been made in culture-dependent and culture-independent techniques. More recently, studies of MDM have relied on culture-independent techniques to recover genetic material through either unicellular genomics or shotgun metagenomics to construct single-amplified genomes (SAGs) and metagenome-assembled genomes (MAGs), respectively, which provide information about evolution and metabolism. Despite the remarkable progress made in the past decades, the functional diversity of MDM still remains uncharacterized. This review comprehensively summarizes the recently developed culture-dependent and culture-independent techniques for characterizing MDM, discussing major challenges, opportunities, and potential applications. These activities contribute to expanding our knowledge of the microbial world and have implications for various fields including Biotechnology, Bioprospecting, Functional genomics, Medicine, Evolutionary and Planetary biology. Overall, this review aims to peel off the layers from MDM, shed light on recent advancements, identify future challenges, and illuminate the exciting opportunities that lie ahead in unraveling the secrets of this intriguing microbial realm.

Combating Cariogenic Streptococcus mutans Biofilm Formation and Disruption with Coumaric Acid on Dentin Surface.

Streptococcus mutans, the primary cause of dental caries, relies on its ability to create and sustain a biofilm (dental plaque) for survival and pathogenicity in the oral cavity. This study was focused on the antimicrobial biofilm formation control and biofilm dispersal potential of Coumaric acid (CA) against Streptococcus mutans on the dentin surface. The biofilm was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) viability assay, microtiter plate assay, production of extracellular polymeric substances (EPSs), florescence microscopy (surface coverage and biomass µm2) and three-dimensional (3D) surface plots. It was observed that CA at 0.01 mg/mL reduced bacterial growth by 5.51%, whereases at 1 mg/mL, a significant (p < 0.05) reduction (98.37%) was observed. However, at 1 mg/mL of CA, a 95.48% biofilm formation reduction was achieved, while a 73.45% biofilm dispersal (after 24 h. treatment) was achieved against the preformed biofilm. The MTT assay showed that at 1 mg/mL of CA, the viability of bacteria in the biofilm was markedly (p < 0.05) reduced to 73.44%. Moreover, polysaccharide (EPS) was reduced to 24.80 µg/mL and protein (EPS) to 41.47 µg/mL. ImageJ software (version 1.54 g) was used to process florescence images, and it was observed that the biofilm mass was reduced to 213 (µm2); the surface coverage was reduced to 0.079%. Furthermore, the 3D surface plots showed that the untreated biofilm was highly dense, with more fibril-like projections. Additionally, molecular docking predicted a possible interaction pattern of CA (ligand) with the receptor Competence Stimulating Peptide (UA159sp, PDB ID: 2I2J). Our findings suggest that CA has antibacterial and biofilm control efficacy against S. mutans associated with dental plaque under tested conditions.