Cardiovascular medications used for comorbid diseases in patients with atrial fibrillation. The JoFib study.

PURPOSE: Many atrial fibrillation (AF) patients use cardiovascular medications for indications other than AF. These medications can affect morbidity and mortality. We aim to investigate the characteristics of AF patients who use different medication classes and their clinical course. METHODS: We collected data from the prospective, multicenter registry, JoFib study. We identified classes of non-AF medications (medications not used for rate control, rhythm control, or anticoagulation), described demographic and clinical characteristics, and investigated AF-related outcomes according to these medication classes. RESULTS: From a total of 2020 patients, five classes of cardiovascular non-AF medications were identified, aspirin, P2Y12 inhibitors, ACE inhibitors/ARBs, statins, and diuretics. The most commonly used non-AF medications were diuretics and ACE inhibitors/ARBs (39.2%, and 39%, respectively). 51% of AF patients took more than one non-AF medication. Multivariable Cox regression analysis demonstrated that ACE inhibitor/ARB therapy independently reduced the risks of all-cause mortality and cardiovascular mortality (aHR 0.50, 95%CI 0.37-0.68; aHR 0.51, 95%CI 0.34-0.75, respectively) and that statin therapy reduced the risk of cardiovascular mortality (aHR 0.68, 95%CI 0.48-0.98) in AF patients. Multivariable logistic regression analysis demonstrated a protective effect of statin therapy against the secondary outcome, clinically relevant non-major bleeding (CRNMB) (adjusted OR 0.62 95%CI 0.42-0.94). CONCLUSION: Our findings suggest a protective effect of ACE inhibitors/ARBs against all-cause and cardiovascular mortality, statins against cardiovascular mortality, and CRNMB in patients with AF. Accordingly, these medications should be encouraged in patients with AF when indicated. Additionally, future research should explore whether these medications should be offered to AF patients more routinely. The study was registered with Clinicaltrials.gov (unique identifier number: NCT03917992, Registration date:14/4/2019).

Residual risk of thromboembolic events despite anticoagulation in Middle Eastern patients with atrial fibrillation. The JoFib study.

OBJECTIVES: To investigate residual risk of thromboembolic events despite anticoagulation in patients with atrial fibrillation form the Middle East. MATERIALS AND METHODS: Using data from the JoFib registry, we described the characteristics of patients treated with anticoagulants (n = 1654) and calculated the incidence rate for thromboembolic events. We constructed multivariable Cox proportional hazard models and calculated the population-attributable fraction to determine clinical factors predictive of residual thromboembolic events. RESULTS: During the one-year follow-up, 57 thromboembolic events occurred (incidence rate 4.1 per 100 person-years). In multivariable time-to-event analysis, prior thromboembolic events (aHR 3.8, 95 %CI 2.2-6.4, p < 0.001) and diabetes (aHR 2.3, 95 %CI 1.3-4.1, p = 0.004) were independently predictive of residual thromboembolism. Percentage of thromboembolic risk attributable to prior thromboembolic events was 30.9 % (95 %CI 13.9-44.6, p = 0.001) and was 37.1 % (95 %CI 8.8-56.6, p = 0.015) for diabetes. Furthermore, the effect of diabetes on thromboembolic events depends on the type of anticoagulant, with diabetes being significantly predictive of thromboembolic events in patients anticoagulated with warfarin (aHR 4.11, 95 %CI 1.81-9.37, p = 0.001), but not non-vitamin K antagonist oral anticoagulants (aHR 1.23, 95 %CI 0.51-2.97, p = 0.643) with a p = 0.045 for interaction. Prior thromboembolism was independently predictive of thromboembolic events in both anticoagulants (aHR 2.67, 95 %CI 1.28-5.58, p = 0.009; aHR 7.33, 95 %CI 3.05-17.65, p < 0.001; respectively; p = 0.084 for interaction). CONCLUSIONS: Middle Eastern patients with atrial fibrillation remain at significant risk of thromboembolism and its recurrence despite anticoagulation, and especially in diabetic patients. Therefore, management should focus on controlling diabetes as well as other modifiable risk factors in addition to antithrombotic therapy.

Atrial resection for T4 non-small cell lung cancer with left atrium involvement: a systematic review and meta-analysis of survival.

PURPOSE: Extended resection for non-small cell lung cancer (NSCLC) with T4 left atrium involvement is controversial. We performed a systematic review and meta-analysis to evaluate the short- and long-term outcomes of this treatment strategy. METHODS: We searched the PubMed database for studies on atrial resection in NSCLC patients. The primary investigated outcome was the effectiveness of the surgery represented by survival data and the secondary outcomes were postoperative morbidity, mortality, and recurrence. RESULTS: Our search identified 18 eligible studies including a total of 483 patients. Eleven studies reported median overall survival and 17 studies reported overall survival rates. The estimated pooled 1, 3, 5-year overall survival rates were 69.1% (95% CI 61.7-76.0%), 21.5% (95% CI 12.3-32.3%), and 19.9% (95% CI 13.9-26.6%), respectively. The median overall survival was 24 months (95% CI 17.7-27 months). Most studies reported significant associations between better survival and N0/1 status, complete resection status, and neoadjuvant therapy. CONCLUSION: Extended lung resection, including the left atrium, for NSCLC is feasible with acceptable morbidity and mortality when complete resection is achieved. Lymph node N0/1 status coupled with the use of neoadjuvant therapies is associated with better outcomes.

Factors Associated With University Students' Attitude Toward Euthanasia.

Although euthanasia has been practiced for thousands of years, a wide controversy still exists around it. This study aimed to assess the attitude of university students toward euthanasia and its associated factors. The study included an online self-administered survey. Survey questions consisted of demographic information, psychological condition, and attitude toward euthanasia. A total of 1,188 students participated in the study. Approximately only one-third of the respondents (34.1%) viewed euthanasia as a moral practice, and just one-quarter (25.3%) supported legalizing it. The main reason for not supporting euthanasia was religious considerations (72.2%), followed by moral considerations (46.5%). Factors that predicted a positive attitude toward euthanasia (p < .05) included undefined religion, being male, feeling lonely, or having suicidal thoughts. Conclusively, the negative attitude toward euthanasia is primarily driven by religious beliefs. Furthermore, gender and psychological status play critical roles in students' attitudes toward euthanasia.

Development of Self-Emulsifying Drug Delivery Systems (SEDDSs) Displaying Enhanced Permeation of the Intestinal Mucus Following Sustained Release of Prototype Thiol-Based Mucolytic Agent Load.

In this study, mucoactive self-emulsifying drug delivery systems (SEDDSs) based on sustained release of N-acetylcysteine (NAC) were developed for providing effective intestinal mucopermeation. Polymeric ionic complexes of NAC were formed with polyethyleneimine (PEI), Eudragit E 100, and Eudragit RS 100 and loaded into a novel SEDDS. The SEDDSs exhibited a stable average size of 75 ± 12 nm (polydispersity index (PDI) < 0.3) and showed a rise in the zeta potential from −17.31 mV to −7.72 mV. On Caco-2 cells, SEDDSs at 1−3% were non-cytotoxic. An average of 91.8 ± 5.4% NAC was released from SEDDSs containing Eudragit E 100 (p ≤ 0.05) and Eudragit RS 100 (p ≤ 0.001) complexes at a significantly slower rate within 80 min, whereas the SEDDS containing PEI released NAC in a matter of seconds. Similarly, the SEDDS complexes revealed a time-dependent reduction in mucus dynamic viscosity of 52.6 ± 19.9%. Consequently, as compared with a blank SEDDS, mucodiffusion revealed about 2- and 1.8-fold significantly greater mucopermeation of SEDDSs anchoring Eudragit E 100−NAC and RS 100−NAC complexes (p ≤ 0.05), respectively. The mucoactive SEDDSs, which steadily released NAC while permeating the mucus, were linked to a significantly increased mucopermeation in vitro as a result of optimal mucolytic targeting.

Hydrolysis kinetics of the prodrug myristyl nicotinate.

Myristyl nicotinate is a prodrug of nicotinic acid. In this research, the kinetics of hydrolysis for myristyl nicotinate was studied in an aqueous phosphate buffer solution within a 5-10 pH range and constant ionic strength at a high temperature which was 80 °C to perform accelerated hydrolysis experiments. The effect of temperature, ionic strength, buffer concentrations, and buffer type was studied. The degradation was monitored using a validated HPLC method. The kinetics of hydrolysis of myristyl nicotinate was also studied in skin and liver homogenates. The hydrolysis was found to follow pseudo-first-order kinetics. The rate constant was calculated from the slope of a linear plot of Ln transformation (Ln) of the remaining parent prodrug concentration versus time. The hydrolysis was found pH- dependent, and a pH rate profile was constructed. Moreover, the hydrolysis rate of the prodrug was found to be buffer species dependent. Carbonate buffer has the most catalytic effect over borate and phosphate buffers. The effect of temperature on the kinetics of hydrolysis of myristyl nicotinate in phosphate buffer at pH 9 at 343, 348, 353, and 358°K was studied. The hydrolysis was found to follow the Arrhenius equation. From the Arrhenius plot, the half-life at 25 °C, and the activation energy were calculated and were found to be 466.5 days and 24.57 kcal mol-1, respectively. The hydrolysis of the prodrug was faster in liver and skin homogenates than those in aqueous buffer solutions. The pseudo-first-order rate constants were found to be 0.012, 0.028 min-1 for myristyl nicotinate in the liver, and skin homogenates, respectively.

Depression Among the Caregivers of Breast Cancer Patients and its Association with the Quality of Life.

Introduction: This study investigated the prevalence of depression among the Jordanian caregivers of patients with breast cancer and its effect on their health-related quality of life (QOL). Methods: This was a cross-sectional study with a sample that consisted of 122 caregivers recruited from 2 hospitals in Jordan over 5 months. A validated questionnaire was used to assess the prevalence of depression symptoms and the aspects of QOL among the participants using Beck's Depression Inventory-II score and the 36-Item Survey Form (SF-36) score. Results and Discussion: Depression symptoms were revealed in 27.9% of caregivers. Regarding the QOL, the mental health (MH) subscale was considerably associated with caregivers' age (P=0.007). The marital status of caregivers was significantly associated with pain (Bodily Pain BP) (P=0.015), Beck's Depression Inventory (BDI; P=0.009), and social functioning (SF) (P=0.008). The number of caregivers' siblings was considerably associated with MH (P=0.040) subscale. The monthly income of caregivers was associated with BP (P=0.042). The residency of caregivers was considerably connected with role limitations because of emotional problems (RE) (P=0.027) and role limitations due to physical health (RF) (P=0.013) subscales. There was a significant correlation between the existing family history of depression with RF (P=0.009), RE (P=0.005), SF (P=0.003), and energy/fatigue (Vitality VT) (P=0.001) subscales. Furthermore, the physical activity of caregivers was connected with the RF (P=0.030), general health (GH) (P=0.018), RE (P=0.015), and MH (P=0.003) subscales. Conclusion: Around a third of the caregivers revealed depression symptoms. The QOL subscales for these caregivers were connected with various health and social factors, such as age, number of siblings, marital status, monthly income, residency, family history of depression, and physical activity. The evaluation of the mental and physical well-being of caregivers should always be considered and managed to help them to cope with their QOL.

Hydroxypropyl Beta Cyclodextrin as a Potential Surface Modifier for Paclitaxel Nanocrystals.

Paclitaxel (PTX) is a hydrophobic chemotherapeutic agent cytotoxic against many serious cancers. This study aimed at designing novel PTX nanocrystals (PTX-NCs) coated with the biocompatible and biodegradable hydroxypropyl-beta-cyclodextrin (HPßCD) polymer with specific characteristics through the formation of a non-inclusion complex. Briefly, PTX-NCs were prepared by the anti-solvent method followed by homogenization. Then, the surface of the prepared PTX-NCs was modified using the HPßCD coat (HPßCD-PTX-NCs). The prepared nanocrystals, both coated and uncoated, were characterized in terms of size, polydispersity index, charge, morphology, and stability. Moreover, the nanocrystals were investigated using powder X-ray diffraction (PXRD), differential scanning calorimeter (DSC), and Fourier transform infrared spectroscopy (FTIR). As well, the in vitro release of PTX from the nanocrystals was determined under conditions similar to the IV route of administration. Furthermore, the tendency of the nanocrystals to induce hemolysis was investigated. Results indicated that the size was about 241.4 and 310.5 nm, the polydispersity index was 0.14 and 0.21, and the zeta potential was about - 22.6 and - 16.4 mV for PTX-NCs and HPßCD-PTX-NCs, respectively. Additionally, the PXRD, FTIR, and DSC profiles can be explained by the NCs' integrity and coat formation. The SEM images showed that both PTX-NCs and HPßCD-PTX-NCs have rod-like structures. Moreover, HPßCD-PTX-NCs had significantly superior in vitro release than both PTX-NCs and PTX. Interestingly, the hemolytic assay showed that HPßCD-PTX-NCs had a more efficient and safer profile than PTX-NCs. This study emphasized that HPßCD could be an interesting candidate for the surface modification of PTX-NCs providing superior properties such as release and safety profiles.

Influence of CYP4F2, ApoE, and CYP2A6 gene polymorphisms on the variability of Warfarin dosage requirements and susceptibility to cardiovascular disease in Jordan.

Cardiovascular diseases are among the leading causes of death worldwide. Many of those diseases require treatment with warfarin, an anticoagulant that has a large high inter and intra-variability in the required doses. The aim of this study is to find if there are any associations between rs2108622 of CYP4F2, rs7412 and rs405509 of ApoE, and rs1801272 of CYP2A6, and CVD and warfarin dose variability. The selected genes and their polymorphisms are involved in many GWAS associated with cardiovascular disease and variability in warfarin treatment. The study sample consisted of 212 Jordanian Cardiovascular patients and 213 healthy controls. DNA was extracted and the Mass ARRAY™ system was used to genotype four selected SNPs within three genes (CYP4F2, ApoE, and CYP2A6). Only one out of the four selected SNPs (ApoE rs7412 SNP) was found to be associated with the risk of cardiovascular disease. Also, this SNP showed significant differences in warfarin initial doses. CYP2A6 rs1801272 SNP was found to be associated with warfarin sensitivity during the initiation phase of therapy and with warfarin responsiveness and INR measurement during the stabilization phase of therapy. This study improves the current understanding of the high inter and intra-variabilities in response to warfarin, including the variety of dosing requirements and the susceptibility to cardiovascular disease in the Jordanian Arab population. Further study on a larger sample and in different ethnic groups could help in improving our understanding of warfarin's pharmacogenetics and its application in personalized medicine.

Perceptions of primary healthcare physicians in Jordan of their role in the COVID-19 pandemic: A cross-sectional study.

BACKGROUND: Following the remarkable spread of coronavirus disease 2019 (COVID-19), worldwide, it quickly became apparent that many public health systems worldwide were not prepared to manage such a pandemic. We aimed to assess the perceptions of primary care physicians (PCPs) in Jordan towards their role during COVID-19. METHODS: A cross-sectional study using a self-administered questionnaire was performed. The study participants included PCPs from the Ministry of Health, academic institutions, and the private sector in Jordan. RESULTS: A total of 221 PCPs participated in the study. Most participants reported not having received any training on infection control (59.7%) or COVID-19 (81%). More than half PCPs (53.4%) felt positive about the way patients received and/or complied with their instructions. More than half PCPs (55.7%) educated their patients on protective measures against COVID-19 infection and considered this as part of their role and responsibility. Over 80% of the participants would apply social distancing, hand sanitation, facial masks, and patient education, but only half (51.1%) reported planning to order COVID-19 test kits. CONCLUSIONS: PCPs had a positive attitude towards controlling COVID-19 infection and showed a willingness to educate patients on how to protect themselves. However, PCPs should be provided special training on COVID-19.

Stem cell-related knowledge and attitudes among physicians in Jordan.

BACKGROUND: Rapid advancement of stem cell (SC) therapies provides both opportunities and risks for patients and physicians alike. Physicians have a role in counselling patients about unproven SC therapies, requiring a basic level of knowledge and access to information about SCs. OBJECTIVE: This study sought to assess SC-related knowledge of and attitudes among physicians in Jordan to elucidate areas of deficiency that can be addressed. METHODS: A cross-sectional survey, comprising questions on demographics and SC knowledge and attitudes, was designed as a scoring system to evaluate physicians' knowledge and attitudes. Participants were recruited from 10 major hospitals in Jordan over 3 months between February and April 2019. The internal consistency of the scoring scales was calculated using Cronbach's alpha reliability coefficient. Gender differences were evaluated with an independent t-test. RESULTS: In total, 382 physicians in Jordan completed the survey (59.9% response rate). They demonstrated a low/moderate level of overall SC knowledge (51.3%), but most lacked confidence in their ability to answer patients' questions about SC therapies (64.7%). However, the total attitude score was moderate/high positive (66.8%) and most were interested in learning more about SCs (80.8%). Male physicians reported significantly more knowledge than females (P < .0001). CONCLUSIONS: This study reveals Jordanian physicians' hesitancy to counsel patients about SC therapies, largely because of gaps in knowledge. However, overall attitudes toward SC research and therapies are positive. The results of this study demonstrate a need to cover SC-related information in medical curricula in Jordan, as well as to support initiatives to regulate SC tourism in Jordan.

Caesarean section delivery from maternal perspective: An exploratory study in Jordan.

AIMS OF THE STUDY: This study aims to determine females' views, experiences and attitudes regarding the caesarean section (CS) and to explore the factors that increase the prevalence of CS in Jordan. DESIGN: This is a cross-sectional study using a questionnaire that was distributed electronically through social media websites. Study participants included 1005 females with a history of at least one CS. Awareness, experiences about CS, complications and reasons for performing CS were investigated. SETTINGS: The participants were recruited from all Jordan cities by social media and emails. FINDINGS: Most of the respondents stated that the source of their knowledge about CS was from the internet (36.2%) followed by family and friends (31.6%). The majority of respondents were satisfied with their CS experience (72.8%). More than half of the participants (56.9%) reported that CS carries no risk for infants. About 53% of respondents stated that the most common reason leading women to choose to give birth via CS is the fear of labour pain. However, the majority of the respondents disagree with performing CS under maternal request (59.2%). CONCLUSIONS AND IMPLICATIONS: This study indicated that Jordanian females do not have reliable sources of information about CS. This leads to lower awareness of CS and its complications, and, as expected, CS is more likely to be performed by privately insured women.

Prevalence Estimates, Severity, and Risk Factors of Depressive Symptoms among Coronary Artery Disease Patients after Ten Days of Percutaneous Coronary Intervention.

BACKGROUND: Depression and cardiovascular disorders are significant determinants of health that affect the quality of life and life expectations. Despite the high importance of depression screening among Coronary Artery Disease (CAD) patients, the time being to assess and treat it remains controversial. OBJECTIVES: This study aims to assess the prevalence estimates and severity of depressive symptoms and determine the risk factors associated with developing such symptoms among CAD patients after ten days of Percutaneous Coronary Intervention (PCI). METHODS: All patients who underwent elective PCI between October 5, 2019, and Mid-March 2020 and diagnosed with CAD were included in this cross-sectional study. CAD was defined as intra-luminal stenosis of ≥ 50% in one or more of the coronary arteries. Depressive symptoms were screened after ten days of the PCI utilizing the patient health questionnaire-9 (PHQ-9) tool. A linear regression model was used to assess the adjusted effects of independent variables on PHQ-9 scores. Electronic medical records, clinical charts, and PCI and echocardiogram reports were reviewed. RESULTS: Out of 385 CAD patients, a total of 335 were included in this study, with a response rate of 87%. The participants' mean (±SD) age was 57.5±10.7 years, 75.2% were males, 43% were current smokers, and 73.7% had below bachelor's education. The prevalence estimates of patients with moderate to severe depressive symptoms (PHQ-9 ≥10) was 34%, mild depression 45.1%, and normal 20.9%. Female gender, low educational level and diabetes mellitus were found to be the significant independent predictors of depression among our cohort with (t(333) = 3.68, p<0.001); (t(333) = 5.13, p<0.001); and (t(333) = 2.79, p=0.042), respectively. CONCLUSION: This study suggests a high prevalence of depressive symptoms among CAD patients after ten days of PCI. Approximately one out of three patients with CAD have significant symptoms of depression, which is an alarming finding for clinicians. Moreover, this study demonstrates a lack of sufficient depression recognition and management in similar study settings. Integration of mental health assessment and treatment among patients with CAD as soon as after PCI is recommended for optimal and effective treatment and to obtain the best outcomes.

Detection of Gene Mutations in Liquid Biopsy of Melanoma Patients: Overview and Future Perspectives.

OPINION STATEMENT: Liquid biopsies are still far from widely implanted in the clinical arena. Issues related to the added sensitivity of this test beyond conventional methods have not been fully resolved. Additionally, issues related to the specificity of these results especially as many cancers may share common mutation need further investigations. One way to resolve this may include the development and testing of large gene panels to add higher specificity. On the other hand, further studies are needed to support the idea that ctDNA or circulating tumor cells may constitute a better representation of the tumor subpopulation that is capable of metastasizing, which will strongly support its clinical value. Finally, survival studies showing a positive impact of this technology will also justify its widespread implementation in clinical practice.

Androgen effect on body weight and behaviour of male and female rats: novel insight on the clinical value.

Androgenic-anabolic steroids (AASs) are synthetic derivative forms of the hormone testosterone. Sustanon® 250 solution for injection is one of those AASs that is used for low hormone levels and is self-administered for recreational purposes. This study was conducted to investigate the effects of sustanon on the body weight of male and female rats. Animals were injected different doses of sustanon (vehicle, 1, 3.2, 10, 32 and 100 mg/kg, I.M., once/week, for 6 weeks), and the weights for each animal were obtained. The rats were observed for agitated/aggressive behaviours every other day. In the present study, sustanon injections at 1, 3.2, 10, 32 and 100 mg/kg treatments did not alter body weight in male rats compared to the control group. However, moderately high and supraphysiological doses of sustanon (3.2, 10 and 32 mg/kg) resulted in a significant increase in body weight after 1 month of weekly treatment in female rats. Aggressive/agitated behaviours were observed only in female rats at the period of weight increase. In conclusion, different doses of sustanon did not alter the body weight in male rats after 6 weeks of treatment but doses of 3.2, 10 and 32 mg/kg resulted in a significant increase in body weight of female rats.

Detection of driver mutations in BRAF can aid in diagnosis and early treatment of dedifferentiated metastatic melanoma.

Dedifferentiated metastatic melanoma can pose a significant diagnostic challenge, especially if the history of primary melanoma is not known or is remote. BRAF and NRAS mutations are common melanoma driver mutations that are usually sequenced to evaluate for treatment targets. We evaluated whether BRAF and NRAS mutational testing could contribute to the diagnosis of dedifferentiated metastatic melanoma when immunostains are negative. Seven patients with melanoma who had an additional diagnosis of poorly differentiated sarcoma with negative melanocytic immunostains were tested for BRAF and NRAS mutations. Three patients showed identical BRAF mutations in the melanoma and the poorly differentiated sarcoma and hence were re-classified as metastatic dedifferentiated melanoma. In these three patients, there was an average delay of 7 months before appropriate testing, workup and treatment for metastatic melanoma was initiated. Two of these patients currently have stable metastatic disease and show sustained therapeutic response to melanoma-specific treatment including BRAF inhibitors. BRAF mutational analysis should therefore be considered in cases of poorly differentiated sarcoma, especially if there is a known history of melanoma or with unusual localization of disease. The administration of melanoma-specific treatments in such dedifferentiated cases can show therapeutic response, highlighting the importance of rendering accurate diagnoses on such cases.

The effect of ERCC1 and ERCC2 gene polymorphysims on response to cisplatin based therapy in osteosarcoma patients.

BACKGROUND: Cisplatin is one of the major drugs that used in the treatment of osteosarcoma. Cisplatin exerts its function by making cisplatin-DNA adducts culminating in cellular death. These adducts found to be repaired by nucleotide excision repair (NER) pathway. This study aimed to evaluate if polymorphisms in two main genes in the NER pathway, excision repair cross-complementing group 1 and 2 (ERCC1 and ERCC2) could affect the histological response to cisplatin based chemotherapy or clinical outcomes, particularly, event free survival (EFS) and overall survival (OS) rates. METHOD: ERCC1 (C118T (rs11615) and C8092A (rs3212986)) and ERCC2 (A751C (rs171140) and G312A (rs1799793)) polymorphisms were analysed in 44 patients with osteosarcoma, who were treated with cisplatin based neoadjuvant chemotherapy. DNA was extracted from patient's formalin-fixed paraffin-embedded (FFPE) samples, patient's genotypes were determined by using polymerase chain reaction-restriction fragment length polymorphism PCR-RFLP assay. The distribution of the patients' genotype and the allele frequencies were reported. The association between each of these genotypes and many clinical and patho-histological parameters (e.g. EFS, OS and patho-histological response to treatment) was examined. The associations between gender, tumor location, presence of metastasis at diagnosis, histological subtypes, and type of neoadjuvant chemotherapy and between the histological response, EFS and OS rates were also examined. RESULTS: This study revealed that there was a positive and significant association between ERCC1 C8092 A genotypes and median EFS rate in years; patients who were carriers of C allele (CC & CA) were found to have longer EFS rates than patients with AA genotype (P value = 0.006) and the median EFS rates were respectively as following: 2.04, 0.24 years. As well, both the presence of metastasis and the histological subtype at the time of diagnosis, were able to affect the EFS rate but not the OS. However, there was a positive correlation between OS rate and the patients' primary response to treatment. CONCLUSIONS: Our results suggested that ERCC1 8092 C allele may play a role as a candidate prognostic marker in patients with osteosarcoma.

The Efficacy and Safety of Immune Checkpoint Inhibitors in Adrenocortical Carcinoma: A Systematic Review and Meta-Analysis.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of different malignancies. However, their efficacy in advanced adrenocortical carcinoma (ACC) remains uncertain. Thus, we conducted a systematic review and meta-analysis to summarize the efficacy and tolerability of ICIs in patients with advanced ACC. We searched PubMed, Scopus, and CENTRAL for studies that used ICIs in ACC. Studies with more than five patients were included in the meta-analysis of the objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and grade 3/4 adverse events. Twenty studies with 23 treatment arms and 250 patients were included. Single-agent anti-PD1 or anti-PD-L1 treatment was utilized in 13 treatment arms, whereas an anti-PD1 or anti-PD-L1 and anti-CTLA4 combination was used in 4 treatment arms. Other anti-PD1- or anti-PD-L1-based combinations were used in five treatment arms. The ORR was 14% (95% CI = 10-19%, I2 = 0%), and the DCR was 43% (95% CI = 37-50%, I2 = 13%). The combination anti-PD1- or anti-PD-L1-based treatment strategies did not correlate with higher responses compared with monotherapy. The median OS was 13.9 months (95% CI = 7.85-23.05), and the median PFS was 2.8 months (95% CI = 1.8-5.4). ICIs have a modest efficacy in advanced ACC but a good OS. Further studies are needed to investigate predictive biomarkers for ICI response and to compare ICI-based strategies with the current standard of care.

Sildenafil Effect on Atrial Natriuretic Peptide Level in Pulmonary Hypertensive Rats.

BACKGROUND: Pulmonary Hypertension (PH) leads to changes in pulmonary vascular architecture, hypertrophy of the right ventricle, and heart failure. Sildenafil is a drug that can modulate PH by inducing smooth muscle relaxation and vasodilation. AIMS: To investigate the ability of sildenafil to alleviate the monocritaline (MCT)-induced PH in rats and to estimate the role and its effect on the atrial natriuretic peptide (ANP) levels. METHODS: 28 adult male rats were divided randomly into four groups: Group A (control group; n=7). Group B (MCT-treated group; n=7) was given a single dose of MCT 60 mg/kg subcutaneously. Group C (The reversal group; n=7) received a single dose of MCT 60 mg/kg subcutaneously for three weeks and then sildenafil at 50 mg/kg/day, given daily for another three weeks. Group D (The prevention group; n=7) simultaneously received a single dose of MCT 60 mg/kg subcutaneously and sildenafil daily at 50 mg/kg for three weeks. RESULTS: The animals in the prevention group showed a significant decrease in ANP levels compared to the reversal and MCT-treated groups. This decrease was associated with a significant reduction in the Fulton index ratio in the prevention group compared to the reversal group. The nitric oxide levels were also significantly higher in the reversal group than in the control group. CONCLUSION: Preventive sildenafil treatment was associated with a significant decrease in ANP levels and reduced MCT-induced cardiac hypertrophy in rats.

Evaluation of Novel HLM Peptide Activity and Toxicity against Planktonic and Biofilm Bacteria: Comparison to Standard Antibiotics.

BACKGROUND: Antibiotic resistance is one of the main concerns of public health, and the whole world is trying to overcome such a challenge by finding novel therapeutic modalities and approaches. This study has applied the sequence hybridization approach to the original sequence of two cathelicidin natural parent peptides (BMAP-28 and LL-37) to design a novel HLM peptide with broad antimicrobial activity. METHODS: The physicochemical characteristics of the newly designed peptide were determined. As well, the new peptide's antimicrobial activity [Minimum Inhibitory Concentration (MIC), Minimum Bacterial Eradication Concentration (MBEC), and antibiofilm activity] was tested on two control (Staphylococcus aureus ATCC 29213, Escherichia Coli ATCC 25922) and two resistant [Methicillin-resistant Staphylococcus aureus (MRSA) ATCC BAA41, New Delhi metallo-beta- lactamase-1 Escherichia coli ATCC BAA-2452) bacterial strains. Furthermore, synergistic studies have been applied to HLM-hybridized peptides with five conventional antibiotics by checkerboard assays. Also, the toxicity of HLM-hybridized peptide was studied on Vero cell lines to obtain the IC50 value. Besides the percentage of hemolysis action, the peptide was tested in freshly heparinized blood. RESULTS: The MIC values for the HLM peptide were obtained as 20, 10, 20, and 20 µM, respectively. Also, the results showed no hemolysis action, with low to slightly moderate toxicity action against mammalian cells, with an IC50 value of 10.06. The Biomatik corporate labs, where HLM was manufactured, determined the stability results of the product by Mass Spectrophotometry (MS) and High-performance Liquid Chromatography (HPLC) methods. The HLM-hybridized peptide exhibited a range of synergistic to additive antimicrobial activities upon combination with five commercially available different antibiotics. It has demonstrated the biofilm-killing effects in the same concentration required to eradicate the control strains. CONCLUSION: The results indicated that HLM-hybridized peptide displayed a broad-spectrum activity toward different bacterial strains in planktonic and biofilm forms. It showed synergistic or additive antimicrobial activity upon combining with commercially available different antibiotics.