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Background: Despite the extensive use of the gonadotropin-releasing hormone (GnRH) antagonist protocol in treating infertile women, particularly those with polycystic ovary syndrome (PCOS), there have not been sufficient evidence to compare the flexible and fixed variants in in vitro fertilization (IVF) cycles. Objective: This study aims to assess the treatment outcomes of flexible and fixed types of GnRH-antagonist protocol for IVF in women with PCOS. Materials and Methods: In this randomized clinical trial, 150 infertile women with PCOS, who were candidates for IVF, and referred to the Yazd Research and Clinical Center for Infertility, Yazd, Iran between October 2023 and February 2024 were included. Participants were divided into 2 groups (n = 75/each) based on the type of antagonist protocol (fixed or flexible). GnRH antagonist administration started on the 5 th day of gonadotropin treatment in the fixed group. In the flexible group when there was at least one follicle 12–14 mm, GnRH antagonist was started. Finally, the number of metaphase II oocyte, the quality of embryos, the duration of the stimulation cycle, the dose of gonadotropin, the number of GnRH-antagonist, and the rate of ovarian hyperstimulation syndrome were evaluated. Results: No statistically significant difference was observed in terms of cycle length and the total dose of gonadotropin between groups. Nevertheless, a notable distinction was observed in the total number of oocytes (17.84 vs. 15.5, p = 0.023) and mature oocytes (13.64 vs. 11.83, p = 0.019) in the flexible group compared to the fixed group. Conclusion: In conclusion, the IVF outcomes are more favorable in women with PCOS undergoing the flexible GnRH-antagonist protocol compared to the fixed protocol.

Abstract Breast cancer is one of the most common cancers in women. One of the best therapeutic methods against breast cancer is gene therapy, while having an appropriate gene carrier is the biggest challenge of gene therapy. Hence, developing carriers with low cytotoxicity and high gene transfection efficiency, and preferentially with the selective function of gene delivery is a critical demand for this method. In the present study, we introduce a novel targeted carrier to deliver the inducible caspase-9 suicide gene (pLVSIN-iC9) into breast cancer cells. The carrier is composed of graphene oxide quantum dots decorated with polyethyleneimine, and S2.2; an aptamer with high affinity to MUC1 (GOQD-PEI/S2.2). Due to the overexpression of MUC1 in breast cancer cells, the designed GOQD-PEI/S2.2/pLVSIN-iC9 can selectively target cancer cells. Moreover, to better mimic solid tumor conditions, and to evaluate the selective effect of the GOQD-PEI/S2.2/pLVSIN-iC9, an organoid model derived from human dermal fibroblasts (HDF) and MCF-7 cells (coculture organoid) was generated and characterized. The results demonstrate that the coculture organoid model adapts the tissue structure of luminal breast cancer, as well. Therefore, the organoids were subjected to treatment with targeted gene therapy using GOQD-PEI/S2.2/pLVSIN-iC9. Our evidence supports the targeted killing effect of iC9 on the breast cancer cells of the organoids and suggests the good potential of the newly introduced carriers in targeted gene delivery.

This paper presents the concept of periodic marine risers, which is investigated in a comprehensive theoretical manner to establish tools for the design and prediction of the performance characteristics of this class of risers. The presented concept of periodic risers introduces an optimally placed and designed array of periodic inserts that reinforce the conventional riser to, on the one hand, enhance its elastic instability threshold to internal flows and, on the other hand, introduce stop/pass band characteristics that can trap the vortex shedding excitations in order to mitigate their effects. Such a concept has not been investigated in the literature. The effectiveness of the concept is investigated and demonstrated theoretically by modeling the dynamics of these risers using finite element analysis and developing their instability threshold to internal flows, as well as their bandgap characteristics by extracting the eigenvalues of the associated transfer matrices. Comparisons are established between the performance characteristics of these periodic risers and conventional risers to demonstrate the merits and limitations of the proposed concept.

Abstract Background Complete surgical removal of pancreatic ductal adenocarcinoma (PDAC) is central to all curative treatment approaches for this aggressive disease, yet this is only possible in patients technically amenable to resection. Hence, an accurate assessment of whether patients are suitable for surgery is of paramount importance. The SCANPatient trial aims to test whether implementing a structured synoptic radiological report results in increased institutional accuracy in defining surgical resectability of non-metastatic PDAC. Methods SCANPatient is a batched, stepped wedge, comparative effectiveness, cluster randomised clinical trial. The trial will be conducted at 33 Australian hospitals all of which hold regular multi-disciplinary team meetings (MDMs) to discuss newly diagnosed patients with PDAC. Each site is required to manage a minimum of 20 patients per year (across all stages). Hospitals will be randomised to begin synoptic reporting within a batched, stepped wedge design. Initially all hospitals will continue to use their current reporting method; within each batch, after each 6-month period, a randomly selected group of hospitals will commence using the synoptic reports, until all hospitals are using synoptic reporting. Each hospital will provide data from patients who (i) are aged 18 or older; (ii) have suspected PDAC and have an abdominal CT scan, and (iii) are presented at a participating MDM. Non-metastatic patients will be documented as one of the following categories: (1) locally advanced and surgically unresectable; (2) borderline resectable; or (3) anatomically clearly resectable (Note: Metastatic disease is treated as a separate category). Data collection will last for 36 months in each batch, and a total of 2400 patients will be included. Discussion Better classifying patients with non-metastatic PDAC as having tumours that are either clearly resectable, borderline or locally advanced and unresectable may improve patient outcomes by optimising care and treatment planning. The borderline resectable group are a small but important cohort in whom surgery with curative intent may be considered; however, inconsistencies with definitions and an understanding of resectability status means these patients are often incorrectly classified and hence overlooked for curative options. Trial registration The SCANPatient trial was registered on 17th May 2023 in the Australian New Zealand Clinical Trials Registry (ANZCTR) (ACTRN12623000508673).

Monkeypox (Mpox), an uncommon zoonotic Orthopoxvirus, is commonly manifested by blisters on the skin and has a mortality rate of approximately 0-10%. Approximately two decades after the cessation of global smallpox vaccination, the number of confirmed cases of Mpox has been growing, making it the most common Orthopoxvirus infection. Therefore, in this narrative review, we aimed to shed light on recent advancements in the pathophysiology, transmission routes, epidemiology, manifestations, diagnosis, prevention, and treatment of Mpox, as well as the application of artificial intelligence (AI) methods for predicting this disease. The clinical manifestations of Mpox, including the onset of symptoms and dermatologic characteristics, are similar to those of the infamous smallpox, but Mpox is clinically milder. Notably, a key difference between smallpox and Mpox is the high prevalence of lymphadenopathy. Human-to-human, animal-to-human, and animal-to-animal transmission are the three main pathways of Mpox spread that must be considered for effective prevention, particularly during outbreaks. PCR testing, as the preferred method for diagnosing Mpox infection, can enhance early detection of new cases and thereby improve infection control measures. JYNNEOS and ACAM2000 are among the vaccines most commonly recommended for the prevention of Mpox. Brincidofovir, Cidofovir, and Tecovirimat are the primary treatments for Mpox cases. Similar to other viral infections, the best approach to managing Mpox is prevention. This can, in part, be achieved through measures such as reducing contact with individuals displaying symptoms, maintaining personal safety, and adhering to practices commonly used to prevent sexually transmitted infections.

Abstract Background: Recently, letrozole has been used to prevent moderate to severe ovarian hyperstimulation syndrome (OHSS) in assisted reproductive technology cycles due to its estrogen-reducing and androgen-increasing effects on the ovaries, affecting granulosa cells, and reducing vascular endothelial growth factor production. Objective: This study aimed to investigate the impact of letrozole consumption in preventing OHSS in infertile women with polycystic ovarian syndrome undergoing in vitro fertilization. Materials and Methods: In this cross-sectional study, among 1743 medical records of infertile women who were scheduled for oocyte retrieval at Research and Clinical Center for Infertility, Yazd, Iran. Data of 343 women with polycystic ovarian syndrome diagnosis and at risk of OHSS was extracted from March 2022–2023. The stimulation was carried out using a flexible gonadotropin releasing hormone (GnRH) antagonist protocol. Women were divided into 2 groups based on whether they received letrozole or not. In the letrozole group, 2.5 mg letrozole twice daily was continued from the trigger day, while in the control group, women did not receive letrozole. The parameters of OHSS severity, hospitalization rates, and the need for albumin prescription were analyzed. Results: 89 women in the letrozole and 254 women in the control group were examined. There was no statistically significant difference between groups in terms of age and body mass index; however, anti-Mullerian hormone was significantly higher than control group (7.53 ± 4.61 vs. 5.47 ± 3.63, p < 0.001). The parameters of OHSS severity, hospitalization rates, and the need for albumin prescription showed no significant differences between the groups. Conclusion: Recent study indicates that incorporating letrozole into the treatment of GnRH antagonists and cabergoline does not reduce the OHSS severity.

Abstract Background Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal types of cancer, and KRAS oncogene occurs in over 90% of cases. P21-activated kinases (PAK), containing six members (PAK1 to 6), function downstream of KRAS. PAK1 and PAK4 play important roles in carcinogenesis, but their combinational effect remains unknown. In this study, we have determined the effect of dual inhibition of PAK1 and PAK4 in PDA progression using knockout (KO) cancer cell lines. Methods Murine wild-type (WT) and PAK1KO pancreatic cancer cell lines were isolated from PAK1+/+ and PAK1−/− KPC (LSL-Kras G12D/+ ; LSL-Trp53 R172H/+ ; Pdx-1-Cre) mice. KPC PAK4KO and KPC PAK1&4 KO cell lines were generated from KPC WT and KPC PAK1KO cell lines respectively using the CRISPR-CAS9 gene knockout technique. PAK WT and KO cell lines were used in mouse models of pancreatic tumours. Cells and tumour tissue were also used in flow cytometry and proteomic studies. A human PDA tissue microarray was stained by immunohistochemistry. Results Double knock out of PAK1 and PAK4 caused complete regression of tumour in a syngeneic mouse model. PAK4KO inhibited tumour growth by stimulating a rapid increase of cytotoxic CD8+ T cell infiltration. PAK1KO synergistically with PAK4KO increased cytotoxic CD8+ T cell infiltration and stimulated a sustained infiltration of CD8+ T cells at a later phase to overcome the immune evasion in the PAK4KO tumour. The human PDA tissue microarray study showed the important role of PAK1 and PAK4 in intra-tumoral T-cell function. Conclusion Our results demonstrated that dual inhibition of PAK1 and PAK4 synergistically suppressed PDA progression by stimulating cytotoxic CD8 + T cell response.

Considering the different side effects of the long-time conventional anti-rheumatic drugs prescribed for the treatment of rheumatoid arthritis, numerous studies have focused on herbal medicines to reduce inflammation in autoimmune diseases. Although the beneficial properties of evening primrose on rheumatoid arthritis have been determined, the results of the studies have not been systematically reported. The present review has investigated the effects of evening primrose on rheumatoid arthritis systematically. We searched the following electronic databases until March 2023: PubMed, the Cochrane Library, the China National Knowledge Infrastructure, Scopus, ProQuest, Google Scholar electronic databases, allied and complementary medicine database (AMED), and scientific information database (SID) databases for relevant studies. We excluded non-English articles and those not meeting our criteria. We chose all of the correlated original clinical, animal, and in vitro studies. Each article was assessed critically for the possible risk of bias. Thirteen articles were analyzed. Animal and in vitro research confirmed the desired effects of evening primrose on clinical, inflammatory, oxidative, and immunologic factors in rheumatoid arthritis. Also, the results of clinical studies showed the change and improvement of inflammatory and oxidative biomarkers in rheumatoid arthritis. Evening primrose could control rheumatoid arthritis in multiple ways such as decreasing inflammation, inhibiting oxidative stress, and modulating the immune system. This article provides convincing evidence to support the efficacy of evening primrose in rheumatoid arthritis and explains the significance of future clinical trials. Further large-scale high-quality randomized controlled trials (RCTs) assessing the efficacy of evening primrose on rheumatoid arthritis as a primary outcome variable are recommended.

Abstract In this study, a gas sensor array along with intensity modulation of UV light was utilized to discriminate several gases at room temperature. The sensor array was consisted of two interdigitated microelectrodes and TiO2 nanofibres were electrospun on them and calcined at 540°C for 90 min. One of these sensors was coated by 2‐nm Pt using the DC sputtering method and the other one remained uncoated. In each experiment, the sensor array was located at a distance of 30 mm from a 365‐nm UV LED. For intensity modulation of UV light, a staircase waveform voltage was applied to the UV LED. The voltage was included of three voltage steps and the measured powers at a distance of 30 mm from the UV‐LED were about 450, 560, and 680 µW/cm2, respectively. Analytes including acetone, ethanol, methanol, 2‐propanol, and carbon monoxide (CO) at various concentrations ranging from 50 to 500 ppm were examined. Three‐dimensional Principal Component Analysis mapping was successfully used for the segregation of all examined gases. The examinations revealed that using sensor array along with intensity modulation of UV light is an effective method for discrimination of several analytes at room temperature.

Objective(s): To determine the microbiological quality of water used in Tehran food industries. Methods: 50 food factories were randomly selected. Free residual chlorine (as an indicator of effective disinfections), Total and Thermotolearant Coliforms (as indicators of contamination) were the main parameters measured in up to 300 water samples taken from water supply systems. The examination of water was performed according to the standard methods described by the American Public Health Association (APHA). Results: The result indicated that 94% of factories had private water supply systems. 92% were used underground water resources. Only 36% of factories disinfected water before use; in most samples, concentrantions of free residual cholrine were not in the optimal range. 47.7% and 10.4% of sample were contaminated; with mean total coliform 3 per 10 ml and mean thermotolearant colifirms counts of 8.6/l00 ml respectively. Conclusion: In general, the management of water quality control (specially microbiological aspect) in Tehran food industries is poor and there is a real need for improvement.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a low 5-year survival rate and is associated with poor response to therapy. Elevated expression of the myeloid-specific hematopoietic cell kinase (HCK) is observed in PDAC and correlates with reduced patient survival. To determine whether aberrant HCK signaling in myeloid cells is involved in PDAC growth and metastasis, we established orthotopic and intrasplenic PDAC tumors in wild-type and HCK knockout mice. Genetic ablation of HCK impaired PDAC growth and metastasis by inducing an immune-stimulatory endotype in myeloid cells, which in turn reduced the desmoplastic microenvironment and enhanced cytotoxic effector cell infiltration. Consequently, genetic ablation or therapeutic inhibition of HCK minimized metastatic spread, enhanced the efficacy of chemotherapy, and overcame resistance to anti-PD1, anti-CTLA4, or stimulatory anti-CD40 immunotherapy. Our results provide strong rationale for HCK to be developed as a therapeutic target to improve the response of PDAC to chemo- and immunotherapy.

Abstract Objective Postoperative complications following major abdominal surgeries is a pressing concern for hospital care and health economics. Given the paucity of available cost data for patients undergoing major abdominal surgery, we evaluated the number and the severity of postoperative complications following major abdominal surgeries and calculated the costs borne by a single centre university hospital within an Australian healthcare system. Results The overall incidence of postoperative complications for 1790 adult patients undergoing major abdominal surgeries (i.e., colonic, liver, small bowel resections and Whipple procedures) between January 2013 and June 2018 was 75.2%. Of these complications, 56.9% were minor (Clavien–Dindo (CVD) Grades I or II) and 15.5% were major (CVD Grades III or IV). As the severity of complications increased, median adjusted total hospital costs rose significantly, with a median (interquartile range [IQR]) of AUD 29,519.70 (IQR 21,828.80–40,527.90) in CVD Grade II versus AUD 50,702.40 (IQR 35,866.00–69,296.80) in CVD Grade III (p

Abstract Green tea polyphenols (GTPs), particularly epigallocatechin-3-gallate, stand out among natural small molecules screened for their ability to target protein aggregates due to their potent anti-amyloidogenic and neuroprotective activities against various disease-related peptides and proteins. However, the clinical applications of GTPs in amyloid-related diseases have been greatly limited by drawbacks such as poor chemical stability and low bioavailability. To address these limitations, this study utilized an Iranian green tea polyphenolic extract as a reducing agent to neutralize silver ions and facilitate the formation of silver nanoparticle capped by GTPs (GTPs-capped AgNPs). The results obtained from this study demonstrate that GTPs-capped AgNPs are more effective than free GTPs at inhibiting amyloid fibrillation and reducing cytotoxicity induced by amyloid fibrils of human insulin and α-synuclein (α-syn). This improved efficacy is attributed to the increased surface/volume ratio of GTPs-capped AgNPs, which can enhance their binding affinity to amyloidogenic species and boosts their antioxidant activity. The mechanism by which GTPs-capped AgNPs inhibit amyloid fibrillation appears to vary depending on the target protein. For structured protein human insulin, GTPs-capped AgNPs hinder fibrillation by constraining the protein in its native-like state. In contrast, GTPs-capped AgNPs modulate fibrillation of intrinsically disordered proteins like α-syn by redirecting the aggregation pathway towards the formation of non-toxic off-pathway oligomers or amorphous aggregates. These findings highlight polyphenol-functionalized nanoparticles as a promising strategy for targeting protein aggregates associated with neurodegenerative diseases.

BackgroundThe concept of a “textbook outcome” is emerging as a metric for ideal surgical outcomes. We aimed to evaluate the impact of an advanced haemodynamic monitoring (AHDM) algorithm on achieving a textbook outcome in patients undergoing hepatobiliary–pancreatic surgery.MethodsThis retrospective, multicentre observational study was conducted across private and public teaching sectors in Victoria, Australia. We studied patients managed by a patient-specific, surgery-specific haemodynamic algorithm or via usual care. The primary outcome was the effect of using a patient-specific, surgery-specific AHDM algorithm for achieving a textbook outcome, with adjustment using propensity score matching. The textbook outcome criteria were defined according to the International Expert Delphi Consensus on Defining Textbook Outcome in Liver Surgery and Nationwide Analysis of a Novel Quality Measure in Pancreatic Surgery.ResultsOf the 780 weighted cases, 477 (61.2%, 95% CI: 57.7%–64.6%) achieved the textbook outcome. Patients in the AHDM group had a higher rate of textbook outcomes [n = 259 (67.8%)] than those in the Usual care group [n = 218 (54.8%); p