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Abstract Background The development of new strategies to inhibit and/or treat osteoporosis as a chronic systemic disease is one of the most crucial topics. The present study aimed to investigate the simultaneous effects of calcium fluoride nanoparticles (CaF2 NPs) and lactobacillus reuteri ATCC PTA 6475 (L. reuteri) against osteoporosis in an ovariectomized rat model (OVX). Methods In this study, 18 matured Wistar female rats were randomly assigned into 6 groups, including control, OVX, sham, OVX + L. reuteri, OVX + CaF2 NPs, and OVX + L. reuteri + CaF2 NPs. We used OVX rats to simulate post-menopausal osteoporosis, and the treatments were begun two weeks before OVX and continued for four weeks. All groups’ blood samples were collected, and serum biomarkers (estrogen, calcium, vitamin D3, and alkaline phosphatase (ALP)) were measured. The tibia and Femur lengths of all groups were measured. Histopathological slides of tibia, kidney, and liver tissues were analyzed using the Hematoxylin and Eosin staining method. Results Our results revealed that dietary supplementation of L. reuteri and CaF2 NPs in low doses for 6 weeks did not show adverse effects in kidney and liver tissues. The tibial and femoral lengths of OVX rats as well as the population of osteoblasts and osteocytes and newly generated osteoid in the tibia remarkably increased in the combination therapy group. Moreover, there was a significant increase in serum estrogen levels and a significant decrease in serum calcium and alkaline phosphatase levels in combination treatment groups compared to the OVX groups not receiving the diet. Conclusions Our results suggest the favorable effects of the simultaneous supplementation of L. reuteri and CaF2 NP to reduce post-menopausal bone loss. Graphical abstract

Introduction: Gastric cancer is one of the most commonly known malignancies and is the fifth cancer-related death globally. Whereas natural killer (NK) cells play a critical role in tumor elimination; therefore, adoptive NK cell therapy has become a promising approach in cancer cytotherapy. Hence, this study investigated the chemo-immune cell therapy in MKN-45 derived xenograft gastric cancer model. Methods: Three groups of animals have received the following treatments separately: activated NK cells, capecitabine, the combination of capecitabine and activated NK cells, and one was considered as the control group. Morphometric properties of tumor samples were evaluated at the end of the study. NK cells infiltration was evaluated by immunohistochemistry (IHC) of hCD56. Mitotic count and treatment response was assessed by hematoxylin and eosin (H&E) staining. The proliferation ratio to apoptosis was determined by IHC assessment of Ki67 and caspase 3. Results: The results indicated that the NK cell therapy could effectively decrease the mitotic count in pathology assessment, but the tumor was not completely eradicated. In combination with metronomic chemotherapy (MC) of capecitabine, NK cell therapy demonstrated a significant difference in tumor morphometric properties compared to the control group. The proliferation ratio to apoptosis was also in line with pathology data. Conclusion: Although NK cell therapy could effectively decrease the mitotic count in vivo, the obtained findings indicated lesser potency than MC despite ex vivo activation. In order to enhance NK cell therapy effectiveness, suppressive features of the tumor microenvironment and inhibitory immune checkpoints blockade should be considered.

ABSTRACT: The objective of this study was to evaluate the effects of varying the ratio of dietary palmitic (C16:0; PA) and stearic (C18:0; SA) acids on nutrient digestibility, production, and blood metabolites of early-lactation Holsteins under mild-to-moderate heat stress. Eight multiparous Holsteins (body weight = 589 ± 45 kg; days in milk = 51 ± 8 d; milk production = 38.5 ± 2.4 kg/d; mean ± standard deviation) were used in a duplicated 4 × 4 Latin square design (21-d periods inclusive of 7-d data collection). The PA (88.9%)- and SA (88.5%)-enriched fat supplements, either individually or in combination, were added to diets at 2% of dry matter (DM) to formulate the following treatments: (1) 100PA:0SA (100% PA + 0% SA), (2) 66PA:34SA (66% PA + 34% SA), (3) 34PA:66SA (34% PA + 66% SA), and (4) 0PA:100SA (0% PA + 100% SA). Diets offered, in the form of total mixed rations, were formulated to be isonitrogenous (crude protein = 17.2% of DM) and isocaloric (net energy for lactation = 1.69 Mcal/kg DM), with a forage-to-concentrate ratio of 40:60. Ambient temperature-humidity index averaged 72.9 throughout the experiment, suggesting that cows were under mild-to-moderate heat stress. No differences in DM intake across treatments were detected (mean 23.5 ± 0.64 kg/d). Increasing the dietary proportion of SA resulted in a linear decrease in total-tract digestibility of total fatty acids, but organic matter, DM, neutral detergent fiber, and crude protein digestibilities were not different across treatments. Decreasing dietary PA-to-SA had no effect on the time spent eating (340 min/d), rumination (460 min/d), and chewing (808 min/d). As dietary PA-to-SA decreased, milk fat concentration and yield decreased linearly, resulting in a linear decrease of 3.5% fat-corrected milk production and milk fat-to-protein ratio. Feed efficiency expressed as kg 3.5% fat-corrected milk/kg DM intake decreased linearly with decreasing the proportion of PA-to-SA in the diet. Treatments had no effect on milk protein and lactose content. A linear increase in de novo and preformed fatty acids was identified as the ratio of PA to SA decreased, while PA and SA concentrations of milk fat decreased and increased linearly, respectively. A linear reduction in blood nonesterified fatty acids and glucose was detected as the ratio of PA to SA decreased. Insulin concentration increased linearly from 10.3 in 100PA:0SA to 13.1 µIU/mL in 0PA:100SA, whereas blood β-hydroxybutyric acid was not different across treatments. In conclusion, the heat-stressed Holsteins in early-lactation phase fed diets richer in PA versus SA produced greater fat-corrected milk and were more efficient in converting feed to fat-corrected milk.

Background & Aim: Feelings of loneliness can affect the mental health of the elderly and lead to cognitive problems. As a potentially effective treatment approach, cognitive-behavioral therapy (CBT) has emerged as an intervention to alleviate loneliness among the elderly. This study aims to determine the effect of CBT on alleviating loneliness among elderly women referred to health centers in Khomeini Shahr. Methods & Materials: This quasi-experimental study was conducted in 2020 on a sample of 60 elderly women who had been referred to health centers in Khomeini Shahr. The participants were conveniently selected and then randomly assigned to either the intervention or control groups. Data were collected using a demographic information form and the Deshiri et al’s loneliness questionnaire, which were administered before, immediately after, and one month after the intervention. The intervention group received eight counseling sessions of CBT that lasted for 60 minutes each, while the control group did not receive any counseling. Data analysis was carried out using the SPSS software version 23, employing descriptive and inferential statistics. Results: The results obtained from conducting a two-way repeated measures analysis of variance (ANOVA) showed a significant statistical difference in the mean score of loneliness resulting from communication with family, the score of emotional symptoms of loneliness and the total score of loneliness in the intervention group before and after the intervention (P0.05). Furthermore, when comparing the mean score of loneliness resulting from communication with friends in the intervention group, no statistically significant difference was observed before and after the intervention (P=0.094). Similarly, no statistically significant difference was observed in the control group (P=0.338). Conclusion: The results of the current study indicate that CBT is an effective approach to alleviate loneliness in elderly women. Therefore, it is suggested that this method be implemented as a means to reduce feelings of loneliness among elderly women.

Introduction: The maturation faith of dendritic cells is restrained by the inflammatory environment and cytokines, such as interleukin-6 and its downstream component. Therefore, introducing the suitable antigen to dendritic cells is crucial. However, reducing the severity of the suppressive tumor microenvironment is indispensable. The present study examined the combination therapy of lymphocyte antigen 6 family member E (LY6E) pulsed mature dendritic cells (LPMDCs) and pioglitazone against colorectal cancer (CRC) to elevate the effectiveness of cancer treatment through probable role of pioglitazone on inhibiting IL-6/STAT3 pathway. Methods: Dendritic cells were generated from murine bone marrow and were pulsed with lymphocyte antigen 6 family member E peptide to assess antigen-specific T-cell proliferation and cytotoxicity assay with Annexin/PI. The effect of pioglitazone on interleukin (IL)-6/STAT3 was evaluated in vitro by real-time polymerase chain reaction (PCR). Afterward, the CRC model was established by subcutaneous injection of CT26, mouse colon carcinoma cell line, in female mice. After treatment, tumor, spleen, and lymph nodes samples were removed for histopathological, ELISA, and real-time PCR analysis. Results: In vitro results revealed the potential of lysate-pulsed dendritic cells in the proliferation of double-positive CD3-8 splenocytes and inducing immunogenic cell death responses, whereas pioglitazone declined the expression of IL-6/STAT3 in colorectal cell lines. In animal models, the recipient of LPMDCs combined with pioglitazone demonstrated high tumor-infiltrating lymphocytes. Elevating the IL-12 and interferon-gamma (IFN-γ) levels and prolonged survival in lysate-pulsed dendritic cell and combination groups were observed. Conclusion: Pioglitazone could efficiently ameliorate the immunosuppressive feature of the tumor microenvironment, mainly through IL-6. Accordingly, applying this drug combined with LPMDCs provoked substantial CD8 positive responses in tumor-challenged animal models.

Abstract Background Treatment of Helicobacter pylori (H. pylori) infection has become challenging following the development of primary antibiotic resistance. A primary therapeutic regimen for H. pylori eradication includes clarithromycin; however, the presence of point mutations within the 23S rRNA sequence of H. pylori contributes to clarithromycin resistance and eradication failure. Thus, we aimed to develop a rapid and precise method to determine clarithromycin resistance-related point mutations using the pyrosequencing method. Methods and results H. pylori was isolated from 82 gastric biopsy samples and minimal inhibitory concentration (MIC) was evaluated using the agar dilution method. Clarithromycin resistance-associated point mutations were detected by Sanger sequencing, from which 11 isolates were chosen for pyrosequencing. Our results demonstrated a 43.9% (36/82) prevalence in resistance to clarithromycin. The A2143G mutation was detected in 8.3% (4/48) of H. pylori isolates followed by A2142G (6.2%), C2195T (4.1%), T2182C (4.1%), and C2288T (2%). Although the C2195T mutation was only detected by Sanger sequencing, the overall results from pyrosequencing and Sanger sequencing platforms were comparable. Conclusions Pyrosequencing could be used as a rapid and practical platform in clinical laboratories to determine the susceptibility profile of H. pylori isolates. This might pave the way for efficient H. pylori eradication upon detection.

Introduction: According to current investigations, there are controversy in our knowledge regarding the safety and efficacy of Vagus Nerve Stimulation (VNS) in children younger than 12 years old. Therefore, we performed this study and aimed to better evaluate the safety and efficacy of VNS in children younger than 12 years. Method: The retrospective study comprised two groups. In the first group, patients (N = 19) underwent VNS implantation procedure and second group, (N = 21) received no VNS implantation. The main study parameters are as follows: (1) Primary outcome evaluated the proportion of cases with >50 % reduction of seizures at the last follow-up. (2) Changes in patients’ status in VNS group after procedure compared to before procedure. (3) Patient's complaints in VNS group compared to control group. Results: Our results demonstrated that there was a significant reduction in the frequency of seizures (per month) in patients 6 months after VNS surgery compared to before VNS surgery (1044.3 ± 1526.7 VS 220.7 ± 421.6; P value = 0.028). 57.9 % of patients underwent VNS showed the response rate of 50 % reduction in seizure frequency. There was significant improvement in memory problem, work/ school limitation, social limitation, and tachycardia 6 months after VNS procedure compared to before VNS procedure in patients. The most common reported side effects were difficulty swallowing (31.5 %) and coughing (31.5 %) followed by stomach discomfort (15.8 %). Conclusion: Considering the significant reduction in the frequency of seizures and improvement of life aspects including in memory problem, work/ school limitation, social limitation, we recommend VNS as an effective treatment modality for drug-resistant epilepsy in children. However, the combination of VNS with other treatment modalities that could improve other aspects of quality such as energy levels, sleep pattern, and feeling management of life is recommended.

Considering menstruation as a crucial factor in females’ health and fertility, any factor that could change its cycle is important. This study was conducted from April 2021 to October 2022 on females who got 3 doses of vaccines against SARS-CoV-2 through different platforms. The participants were requested to provide the trained experts with any changes regarding menstrual cycles after each dose of the vaccine up to 6 months after the booster shots. The disturbances related to the vaccines were identified by the adverse events committee to find possible associations with the applied vaccines. Of 308 women who participated until the end of the study, 22 (7.1%) complained about at least one abnormality in their menstrual patterns. The most common disturbance was metrorrhagia as 10 (48%) incidences followed by menorrhagia as 6 events (24.2%). Notably, the identified complaints were persistent in 59% of the patients. In addition, 14 studied cases developed COVID-19 infection after menstrual disorders. In these cases, COVID-19 could also play a role in the persistence of postvaccine menstrual disturbances. COVID-19 vaccination could affect menstrual cycle in women with no remarkable previous medical history. More longitudinal studies are required regarding this issue.

Adherent-invasive Escherichia coli (AIEC) pathobionts, which are characterized by their ability to adhere to and invade intestinal epithelial cells, are associated with the etiopathogenesis of inflammatory bowel diseases (IBDs). Outer membrane vesicles (OMVs) released by AIEC strains can facilitate the interaction of these bacteria with host cells through delivering bacterial effectors. The aim of this study was to determine the ability of OMVs derived from AIEC strain LF82 to induce the host immune response, leading to production of proinflammatory cytokines and also altering the gene expression of junction-associated proteins in the human epithelial colorectal adenocarcinoma Caco-2 cell line. OMVs were extracted from AIEC strain LF82, and the cell viability of Caco-2 cells treated with these vesicles was assessed by MTT assay. The morphology and size distribution of vesicles were analyzed using transmission electron microscopy and dynamic light scattering, respectively. Gene expression of occludin, ZO-1, claudin-2, E-cadherin, TLR-2, and TLR-4 in response to OMVs was assessed in Caco-2 cells by RT-qPCR. Moreover, the secretion of IL-8 and TNF-α into the supernatant of Caco-2 cells upon treatment with OMVs was measured using ELISA. Our results demonstrated that OMVs upregulated the gene expression level of TLRs and also altered the gene expression level of junction-associated proteins. OMVs derived from AIEC may play a major role in the promotion of intestinal inflammation and epithelial barrier dysfunction. However, further investigations are needed to elucidate the putative role of OMVs in the pathogenesis of AIEC and IBD.

Abstract Nowadays, an estimated 15% of couples are having trouble conceiving. Infertility is not only a reproductive health problem, but also a social problem that affects family and other interpersonal relationships. Infertility involves psychological problems for both partners. There is a correlation between psychological factors and infertility. It seems that the main cause of infertility can be psychological rather than biological factors. Anxiety, depression, stress associated with infertility and antidepressants used in these patient can impact in the treatment of infertility and their outcomes. Persistent fertility problem will have several negative influences on a couple's life and may cause relationship breakdown. Therefore, more research should be conducted on the reasons of infertility as a way to find the factors related to infertility and reduce its impact.

Abstract Background Approximately 5% of colorectal cancers (CRCs) are hereditary. Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), is the most common form of recognized hereditary CRC. Although Iran, as a developing country, has a high incidence of CRC, the spectrum of variants has yet to be thoroughly investigated. Aims This study aimed to investigate pathogenic and non‐pathogenic variants in MLH1 and MSH2 genes in Iranian patients with suspected Lynch syndrome (sLS). Methods and results In the present study, 25 peripheral blood samples were collected from patients with sLS and high microsatellite instability (MSI‐H). After DNA extraction, all samples underwent polymerase chain reaction and Sanger sequencing to identify the variants in the exons of MLH1 and MSH2 genes. The identified variants were interpreted using prediction tools, and were finally reported under ACMG guidelines. In our study population, 13 variants were found in the MLH1 gene and 8 in the MSH2 gene. Interestingly, 7 of the 13 MLH1 variants and 3 of the 8 MSH2 variants were novel, whereas the remaining variants were previously reported or available in databases. In addition, some patients with sLS did not have variants in the exons of the MLH1 and MSH2 genes. The variants detected in the MLH1 and MSH2 genes had specific characteristics regarding the number, area of occurrence, and their relationship with demographic and clinicopathologic features. Conclusion Overall, our results suggest that analysis of MLH1 and MSH2 genes alone is insufficient in the Iranian population, and more comprehensive tests are recommended for detecting LS.

Objective This study explored nurses’ perceptions of the core competencies required for providing postresuscitation care in both in-hospital and out-of-hospital cardiac arrest.Design Qualitative conventional content analysis.Participants 17 nurses selected with purposeful sampling method.Setting Three educational hospitals in northwest of Iran.Data collection and analysis Semi-structured interviews were used for data collection and they were analysed using conventional content analysis.Results Seven main categories have emerged from the data. The core competencies for nurses providing postresuscitation were identified as: quality assurance, providing evidence-based care, monitoring and presence, situation management, professionalism, positive attitude and providing family centred care.Conclusions The postresuscitation period is a unique and critical time requiring highly competent nursing care. Several core competencies for providing high-quality nursing care during postresuscitation period were identified through nurses’ experience in caring for patients postresuscitation.

Gastrointestinal (GI) cancers comprise a significant number of cancer cases worldwide and contribute to a high percentage of cancer-related deaths. To improve survival rates of GI cancer patients, it is important to find and implement more effective therapeutic strategies with better prognoses and fewer side effects. The development of new drugs can be a lengthy and expensive process, often involving clinical trials that may fail in the early stages. One strategy to address these challenges is drug repurposing (DR). Drug repurposing is a developmental strategy that involves using existing drugs approved for other diseases and leveraging their safety and pharmacological data to explore their potential use in treating different diseases. In this paper, we outline the existing therapeutic strategies and challenges associated with GI cancers and explore DR as a promising alternative approach. We have presented an extensive review of different DR methodologies, research efforts and examples of repurposed drugs within various GI cancer types, such as colorectal, pancreatic and liver cancers. Our aim is to provide a comprehensive overview of employing the DR approach in GI cancers to inform future research endeavors and clinical trials in this field.

Abstract Introduction Hemorrhagic complications of arachnoid cysts have been reported, extensively presenting with subdural or intracystic hematoma after trauma, but presentation with extradural hemorrhage is very rare. In this paper, we report the case of a patient with an arachnoid cyst who developed an extradural hematoma after a subtle head injury. Our patient presented with very mild symptoms in spite of the very large size of the hematoma. Case presentation Our patient was a 23-year-old Iranian man who complained of diffuse progressive headache and vomiting after mild head trauma. A brain computerized scan showed a very large extradural hematoma in the left frontotemporoparietal convexity over a large arachnoid cyst. Conclusion Brain parenchyma containing an arachnoid cyst is vulnerable to trauma and increases the risk of serious hemorrhagic complications. We also suggest that the abnormal shape of the head should be considered as an indication for a computerized tomography scan in cases of mild head injury.

Abstract A number of cagPAI genes in the Helicobacter pylori genome are considered the most evolved genes under a diversifying selection and evolutionary pressure. Among them, cagI and cagN are described as a part of the two different-operon of cagPAI that are involved in the T4SS machinery, but the definite association of these factors with clinical manifestations is still unclear. A total of 70 H. pylori isolates were obtained from different gastroduodenal patients. All isolates were examined for the presence of primary H. pylori virulence genes by PCR analysis. Direct DNA sequence analysis was performed for the cagI and cagN genes. The results were compared with the reference strain. The cagI, cagN, cagA, cagL, vacA s1m1, vacA s1m2, vacA s2m2, babA2, sabA, and dupA genotypes were detected in 80, 91.4, 84, 91.4, 32.8, 42.8, 24.4, 97.1, 84.3, and 84.3% of the total isolates, respectively. The most variable codon usage in cagI was observed at residues 20–25, 55–60, 94, 181–199, 213–221, 241–268, and 319–320, while the most variable codon usage in CagN hypervariable motif (CagNHM) was observed at residues 53 to 63. Sequencing data analysis of cagN revealed a hypothetical hexapeptide motif (EAKDEN/K) in residues of 278–283 among six H. pylori isolates, which needs further studies to evaluate its putative function. The present study demonstrated a high prevalence of cagI and cagN genes among Iranian H. pylori isolates with gastroduodenal diseases. Furthermore, no significant correlation between cagI and cagN variants and clinical diseases was observed in the present study. However, all patients had a high prevalence of cagPAI genes including cagI, cagN, cagA, and cagL, which indicates more potential role of these genes in disease outcome.

Abstract Background Glioblastoma multiforme (GBM) is associated with remarkably poor prognosis, and its treatment is challenging. This investigation aimed to evaluate the safety of suicide gene therapy using allogeneic adipose tissue-derived mesenchymal stem cells (ADSCs) carrying herpes simplex virus-thymidine kinase (HSV-TK) gene for the first time in patients with recurrent GBM. Methods This study was a first-in-human, open-label, single-arm, phase I clinical trial with a classic 3 + 3 dose escalation design. Patients who did not undergo surgery for their recurrence were included and received this gene therapy protocol. Patients received the intratumoral stereotactic injection of ADSCs according to the assigned dose followed by prodrug administration for 14 days. The first dosing cohort (n = 3) received 2.5 × 105 ADSCs; the second dosing cohort (n = 3) received 5 × 105 ADSCs; the third dosing cohort (n = 6) received 10 × 105 ADSCs. The primary outcome measure was the safety profile of the intervention. Results A total of 12 patients with recurrent GBM were recruited. The median follow-up was 16 (IQR, 14-18.5) months. This gene therapy protocol was safe and well tolerated. During the study period, eleven (91.7%) patients showed tumor progression, and nine (75.0%) died. The median overall survival (OS) was 16.0 months (95% CI 14.3–17.7) and the median progression-free survival (PFS) was 11.0 months (95% CI 8.3–13.7). A total of 8 and 4 patients showed partial response and stable disease, respectively. Moreover, significant changes were observed in volumetric analysis, peripheral blood cell counts, and cytokine profile. Conclusions The present clinical trial, for the first time, showed that suicide gene therapy using allogeneic ADSCs carrying the HSV-TK gene is safe in patients with recurrent GBM. Future phase II/III clinical trials with multiple arms are warranted to validate our findings and further investigate the efficacy of this protocol compared with standard therapy alone. Trial registration: Iranian Registry of Clinical Trials (IRCT), IRCT20200502047277N2. Registered 8 October 2020, https://www.irct.ir/ .

Abstract Clostridioides difficile, which causes life-threatening diarrheal disease, is considered an urgent threat to healthcare setting worldwide. The current standards of care solely rely on conventional antibiotic treatment, however, there is a risk of promoting recurrent C. difficile infection (rCDI) because of the emergence of antibiotic-resistant strains. Globally, the alarming spread of antibiotic-resistant strains of C. difficile has resulted in a quest for alternative therapeutics. The use of fecal microbiota transplantation (FMT), which involves direct infusion of fecal suspension from a healthy donor into a diseased recipient, has been approved as a highly efficient therapeutic option for patients with rCDI. Bacteriophages or phages are a group of viruses that can infect and destroy bacterial hosts, and are recognized as the dominant viral component of the human gut microbiome. Accumulating data has demonstrated that phages play a vital role in microbial balance of the human gut microbiome. Recently, phage therapy and fecal virome transplantation (FVT) have been introduced as promising alternatives for the treatment of C. difficile -related infections, in particular drug-resistant CDI. Herein, we review the latest updates on C. difficile- specific phages, and phage-mediated treatments, and highlight the current and future prospects of phage therapy in the management of CDI.