Design, synthesis, and computational analysis (molecular docking, DFT, MEP, RDG, ELF) of diazepine and oxazepine sulfonamides: biological evaluation for in vitro and in vivo anti-inflammatory, antimicrobial, and cytotoxicity predictions.

We report the synthesis and extensive characterization of Diazepane and Oxazepane derivatives, followed by their biological evaluation. These compounds were assessed for in vitro and in vivo antimicrobial, anti-inflammatory, and anticancer activities. Among the synthesized molecules, compound 5b demonstrated remarkable antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis with MIC values of 20 and 40 µg/mL, respectively. Additionally, 5b exhibited potent anti-inflammatory effects both in vitro and in vivo. Advanced computational studies, including DFT, MEP, RDG, and ELF analyses, were performed to understand the electronic distribution and molecular interactions. The bioactivity and physicochemical properties of these derivatives were further predicted using PASS and pkCSM platforms, emphasizing their potential as promising lead molecules in drug development.

Outcome of left main stem percutaneous coronary intervention in a UK nonsurgical center: A 5-year clinical experience.

OBJECTIVES: To evaluate the outcome of unprotected left main stem (LMS) percutaneous coronary intervention (PCI) in a large UK nonsurgical center. BACKGROUND: PCI on unprotected LMS is increasingly regarded as a viable alternative to coronary artery bypass grafting (CABG) with comparable outcome and safety profile in select groups. The safety and efficacy of unprotected LMS PCI without on-site surgical back up has not been reported. METHODS: Data on all unprotected LMS PCI performed between January 2011 and December 2015, was collected from the local PCI database and electronic patient records. In hospital and 1-year major adverse cardiovascular events (MACE) (all-cause mortality, myocardial infarction [MI], stroke, and target vessel revascularization [TVR]) was recorded. RESULTS: 249 patients had unprotected LMS intervention during the study period. 77% of patients (n = 192) were male and mean age was 70 ± 12 years. 31% (n = 78) of cases were elective, 44% (n = 109) NSTEMI, and 25% (n = 62) STEMI. Anatomical distribution: 19% (n = 47) ostial left main, 31% (n = 77) shaft, and 50% (n = 125) bifurcation. The mean SYNTAX score was 24.4 ± 10.6. 22% (n = 55) of patients had severe LV impairment preprocedure and 13% (n = 33) were in cardiogenic shock at presentation. 35% (14%) required IABP support. The vast majority (98.4%) of procedures were successful. No patients required emergency transfer for CABG surgery. There were 25 (10%) in-hospital deaths. 68% of in-hospital deaths occurred in patients undergoing primary PCI for STEMI. 72% of patients who died were in cardiogenic shock at presentation. The 12-month MACE rate was 17.2%. Death occurred in 11.6%, MI in 2.4%, TVR in 2.4%, and stroke in 0.8% of patients. CONCLUSION: These results highlight the safety and efficacy of unprotected LMS PCI in a high volume non-surgical center.

Antibiotics and Imiquimod for Cutaneous T-Cell Lymphoma in Veterans: A Patient Population with Agent Orange Exposure.

LESSONS LEARNED: Staphylococcus aureus infection in cutaneous T-cell lymphoma (CTCL) is thought to contribute to disease progression; thus, adjunctive treatment with antibiotics warrants further investigation. This trial of antibiotic therapy followed by imiquimod in early stage CTCL was not completed because of difficulties with patient accrual. BACKGROUND: Cutaneous T-cell lymphoma (CTCL), a form of non-Hodgkin lymphoma, is a heterogeneous group of malignancies of mature memory T lymphocytes. It has an annual age-adjusted incidence of 7.5 per million persons in the U.S. population [1]. The etiology of CTCL is unknown, but epidemiological studies have reported potential associations with environmental and occupational factors, including Agent Orange exposure in Vietnam Veterans [2]. Both topical and systemic therapies have been identified as effective in CTCL; the choice of treatment is dependent on disease stage, with the overall goal of improving symptoms given the chronic and recurrent nature of the disease. Several studies have suggested that CTCL is exacerbated by the presence of Staphylococcus aureus in the skin and can be ameliorated by treatment with antibiotics [3]. METHODS: Our study was designed to assess the effects of antibiotics and imiquimod on early stage CTCL. Patients between the ages of 30-89 years with stage I and II CTCL were eligible for enrollment. They could not be receiving concurrent therapy, and the study design included a 14-day washout period after discontinuation of CTCL therapy. The washout period was followed by doxycycline 100 mg p.o. b.i.d. for 14 days and then two packets (250 mg per packet) of imiquimod 5% cream topically to the most clinically active lesions 3 days a week (Monday, Wednesday, and Friday) for 28 days. Skin lesions were measured using the modified Severity Weighted Assessment Tool (mSWAT). RESULTS: Our study enrolled only two patients with early stage CTCL because of difficulty locating patients with active CTCL able to discontinue all therapy. The two enrolled patients completed all therapy. One patient had a complete response after imiquimod, whereas the other patient had stable disease. CONCLUSION: Antibiotics and imiquimod have reported activity as single agents in CTCL; we did not enroll enough patients to assess value in the sequence of antibiotic therapy followed by imiquimod.

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden.

Teledermatology as a Tool for Preoperative Consultation Before Mohs Micrographic Surgery Within the Veterans Health Administration.

BACKGROUND: Telemedicine is improving access to subspecialty care within the Veterans Health Administration (VHA). Mohs micrographic surgery (MMS) is a surgical modality used to treat nonmelanoma skin cancers. OBJECTIVE: This study evaluates the use of teledermatology for preoperative consultation for MMS. METHODS AND MATERIALS: A retrospective analysis of interfacility MMS referrals to the Bronx Veterans Affairs Medical Center (VAMC) was conducted. The consult failure rates (CFRs), treatment follow-through rates, time to treatment, and travel savings for "face-to-face" preoperative consults were compared with store-and-forward "teledermatology" preoperative consults. RESULTS: Although both "teledermatology" and "face-to-face" preoperative consults resulted in an equivalent percentage of treated lesions, teledermatology had a significantly decreased CFR. In addition, teledermatology decreased the time to treatment by 2 weeks, increased the percentage of lesions treated within 60 days, and resulted in average travel savings of 162.7 minutes, 144.5 miles, and $60.00 per person. CONCLUSION: This study demonstrates that teleconsultation is effective for preoperative consults for MMS within the VHA system. Teledermatology improved access measures such as time to treatment and travel burden. This program may serve as a model not only for other VAMCs that accept interfacility MMS consults, but also for VAMCs that provide other types of access-limited subspecialty care.

Procedural Results and Long-term Outcome of Chronic Total Occlusion Percutaneous Coronary Intervention in a UK Non-surgical Centre.

Background: Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has evolved a great deal over recent years, with increased procedural success and lower complication rates being reported. This study aims to evaluate the feasibility, safety and success of a dedicated CTO programme in a large UK PCI centre without on-site cardiothoracic surgery facilities. Methods: Clinical and procedural data were retrospectively collected for consecutive unselected patients undergoing CTO PCI between 2015 and 2019 from the local database and regional electronic patient records. In-hospital outcomes and long-term major adverse cardiovascular events (all-cause mortality, MI, stroke and target vessel revascularisation) were recorded. Results: A total of 170 patients underwent 191 CTO procedures during the study period. The mean age was 63 ± 10 years and 80.6% of patients were male (n=137). The clinical indications were: stable chronic coronary syndromes in 88.5% (n=169) of patients; staged procedures in the context of acute coronary syndromes in 1.6% (n=3); and presentation with acute coronary syndrome in 9.9% (n=19). The procedural success rate was 50.0% (n=25) for general interventional cardiologists and 90.1% (n=127) for dedicated CTO operators. In-hospital major adverse cardiovascular events occurred once (0.5%) and interhospital transfer for emergency salvage cardiac surgery was not required. Long-term follow-up data at a median duration of 3.8 years revealed 4 (2.4%) cardiac deaths, 14 (8.3%) spontaneous MI events and 10 (5.9%) target vessel revascularisations. Conclusion: These data suggest CTO PCI using contemporary techniques is both safe and effective when undertaken in a high-volume non-surgical centre by experienced operators.

Impact of paramedic education on door-to-balloon times and appropriate use of the primary PCI pathway in ST-elevation myocardial infarction.

OBJECTIVE: Evidence supports improved outcomes and reduced mortality with rapid reperfusion through primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI). UK national audit data (Myocardial Ischaemia National Audit Project [MINAP]) demonstrates minor improvements in door-to-balloon times (DTB) of <90 min but increasing call-to-balloon times (CTB). We evaluate the effect of a regional Cardiologist delivered paramedic education programme (PEP) on DTB times and appropriate use of the PPCI pathway. METHODS: This was a prospective single-centre study of patients with STEMI brought directly to hospital via ambulance services. Data sources included ambulance charts, in-patient notes, British Cardiovascular Interventional Society (BCIS) database and local MINAP data. All DTB breaches were investigated. A local PEP was implemented with focus on ECG interpretation, STEMI diagnosis and appropriate use of the PPCI pathway. Non-parametric Wilcoxon rank test was used for comparisons of DTB and CTB times between direct versus ED-associated cath lab transfer. RESULTS: A total of 728 patients with STEMI were admitted directly to our centre via ambulance, 66% (n=484) directly to the Catheterisation Laboratory (Cath Lab) and 34% (n=244) via the Emergency Department (ED). There was a significant increase in median DTB, 83 vs 37 min (p<0.001) and median CTB 144 vs 97.5 min (p<0.001) when transfer to the Cath Lab occurred via the ED versus direct transfer. The PEP increased direct cath lab transfers (52%-85%) and generated annual reductions in median DTB times, with sustained improvement seen throughout the 7-year study period. CONCLUSIONS: Paramedic education increases direct transfer of STEMI patients to the Cath Lab, and reduces DTB times. This is an effective and reproducible intervention to facilitate timely reperfusion in STEMI.

Verruciform xanthoma in the setting of cutaneous trauma and chronic inflammation: report of a patient and a brief review of the literature.

We report a rare case of multiple, co-exisitng verruciform xanthomas (VXs) of the anogenital region in the setting of cutaneous trauma. VX is a rare benign mucocutaneous neoplasm that typically presents as a solitary lesion with a predilection for the oral cavity, although extra-oral lesions have been reported involving the vulva, scrotum, penis, anal region and extremities. The etiology and pathogenesis of VX have yet to be determined; however, recent literature has reported that multifocal cutaneous VX are frequently associated with pre-existing inflammatory processes. A significant number of VXs of the skin have been found to co-exist with cutaneous disorders including graft vs. host disease, discoid lupus erythematosus, pemphigus vulgaris, and recessive dystrophic epidermolysis bullosa. Therefore, we speculate severe cutaneous trauma and chronic inflammation may induce epithelial keratinocytes to respond aberrantly leading to epidermal hyperplasia and foamy cell formation characterizing the VX lesion.

Diagnosis and treatment of tick infestation and tick-borne diseases with cutaneous manifestations.

Hard and soft ticks may be associated directly or indirectly with a number of dermatoses, both infectious and inflammatory in origin. Morbidity may occur as a result of tick bites, tick toxicosis, and even infestation. These arthropod vectors may transmit life-threatening protozoan, bacterial, rickettsial, and viral diseases with systemic and cutaneous findings. Additionally, ticks may transmit more than one pathogen with subsequent human coinfection. This article reviews the presentation of tick-borne illnesses and the medical management of these diseases. Among others, diseases such as ehrlichiosis, anaplasmosis, babesiosis, tularemia, borrelioses, tick-borne encephalitides, rickettsial spotted fevers, and tick typhus are discussed in this article. The recognition of skin manifestations associated with these diseases is paramount to early diagnosis and treatment initiation.

Mite infestations.

Mite infestations are important in dermatology because these may cause dermatologic diseases that range from papulosquamous eruptions to urticarial lesions to bullous eruptions and may spread infectious diseases. These clinical manifestations are important to recognize because mite-associated diseases may have systemic complications and may be confused with other dermatologic conditions. In treating mite infestations, oral antibiotics may be necessary. Prevention of infestation may be accomplished by pre-treating clothing with permethrin, using insect repellent N,N-Diethyl-meta-toluamide on clothing and skin, and treating animals infected with mites. This article will review etiology, clinical manifestation, and treatment of mite infestations.

A Study on Capabilities Required In Military Medicine to Develop Modular Training Courses: A Qualitative Study.

INTRODUCTION: The main mission of military medicine in the world is to support the health and treatment of the military in relation to issues, risks, injuries and diseases that arise due to the specific occupational conditions. The current study was carried out with the aim of determining the required skills of military physicians to define and determine the required training modules. METHODS: The study was a qualitative research. Semi-structured interviews were used to collect the data and qualitative content analysis was used to analyze the data. The study population included all the professors and experts in the field of military medicine and medical sciences at the medical universities of Tehran. Snowball sampling technique was used to sample the study participants. RESULTS: Based on the results, the required skills of military physicians in 5 categories and 29 sub- categories were identified; then based on the identified skills, 60 training modules at two introductory and advanced levels were determined including 39 introductory levels and 21 advanced levels. CONCLUSION: We can conclude that some of the important skills that military physicians need and can achieved through training have not been provided in any educational program and to achieve such skills and capabilities, other programs should be developed and modular training can be one of them.

Pravastatin-Induced Eczematous Eruption Mimicking Psoriasis.

BACKGROUND: Statins, an example of the most commonly prescribed medications to the elderly, are not without side effects. Dermatologic events are often overlooked as arising from medications, particularly those which are taken chronically. Moreover, elderly patients are prone to pharmacologic interactions due to multiple medications. In this report, we describe a case of a statin-induced eczematous dermatitis with a psoriasis-like clinical presentation and review the skin manifestations that may arise from statin therapy. CASE PRESENTATION: An 82-year-old man with gout and hypercholesterolemia presented to dermatology clinic with new onset of pruritic, scaly erythematous plaques bilaterally on the extensor surfaces of his arms. He had never had similar lesions before. Despite various topical and systemic treatments over several months, the rash continued to evolve. The patient was then advised to discontinue his long-term statin, which led to gradual resolution of his symptoms. He was subsequently diagnosed with statin-induced eczematous dermatitis. CONCLUSIONS: This case report describes an adverse cutaneous reaction to statins that is rarely reported in the literature. Medications, including longstanding therapies, should be suspected in cases of refractory dermatologic lesions.

Differential gene expression in abdomens of the malaria vector mosquito, Anopheles gambiae, after sugar feeding, blood feeding and Plasmodium berghei infection.

BACKGROUND: Large scale sequencing of cDNA libraries can provide profiles of genes expressed in an organism under defined biological and environmental circumstances. We have analyzed sequences of 4541 Expressed Sequence Tags (ESTs) from 3 different cDNA libraries created from abdomens from Plasmodium infection-susceptible adult female Anopheles gambiae. These libraries were made from sugar fed (S), rat blood fed (RB), and P. berghei-infected (IRB) mosquitoes at 30 hours after the blood meal, when most parasites would be transforming ookinetes or very early oocysts. RESULTS: The S, RB and IRB libraries contained 1727, 1145 and 1669 high quality ESTs, respectively, averaging 455 nucleotides (nt) in length. They assembled into 1975 consensus sequences--567 contigs and 1408 singletons. Functional annotation was performed to annotate probable molecular functions of the gene products and the biological processes in which they function. Genes represented at high frequency in one or more of the libraries were subjected to digital Northern analysis and results on expression of 5 verified by qRT-PCR. CONCLUSION: 13% of the 1965 ESTs showing identity to the A. gambiae genome sequence represent novel genes. These, together with untranslated regions (UTR) present on many of the ESTs, will inform further genome annotation. We have identified 23 genes encoding products likely to be involved in regulating the cellular oxidative environment and 25 insect immunity genes. We also identified 25 genes as being up or down regulated following blood feeding and/or feeding with P. berghei infected blood relative to their expression levels in sugar fed females.

Usefulness of fractional flow reserve measurements to defer revascularization in patients with stable or unstable angina pectoris, non-ST-elevation and ST-elevation acute myocardial infarction, or atypical chest pain.

This study determined the safety of deferring coronary revascularization based on a fractional flow reserve (FFR) value > or = 0.75 in a series of consecutive unselected coronary patients with moderate coronary lesions, including patients with unstable angina, myocardial infarction (MI), and/or positive noninvasive test findings. The study included 201 consecutive coronary patients (mean age 62 +/- 10 years; 65% men) with 231 lesions evaluated by FFR measurement for which revascularization was deferred based on a FFR value > or = 0.75. Lesions associated with a positive noninvasive test result were those located in an artery supplying a myocardial territory in which myocardial ischemia was demonstrated by a noninvasive test. Cardiac events (cardiac death, MI, revascularization) and Canadian Cardiovascular Society angina class were evaluated at follow-up. Indications for coronary angiography included unstable angina or MI (62%), stable angina (30%), or atypical chest pain (8%). Forty-four patients (22%) had > or = 1 coronary lesion associated with a positive noninvasive test result in which FFR was evaluated. Mean FFR value was 0.87 +/- 0.06 and mean lesion percent diameter stenosis was 41 +/- 8%. At 11 +/- 6 months of follow-up, cardiac events occurred in 20 patients (10%), and no significant differences were observed between patients with unstable angina or MI and those with stable angina (9% vs 13%, p = 0.44) or between patients with and without lesions associated with positive noninvasive test results (9% vs 10%, p = 1.00). At the end of follow-up, 88% of patients were asymptomatic in angina class 0 or I, with no differences across various groups. In conclusion, these results suggest that patients with moderate coronary lesions can be safely managed without revascularization on the basis of FFR measurements, irrespective of clinical presentation and/or presence of positive noninvasive test results.

Effect of CaCO3/HCl pretreatment on the surface modification of chitin gel beads via graft copolymerization of 2-hydroxy ethyl methacrylate and 4-vinylpyridine.

Although chitin, poly(N-acetylglucosamine), possesses considerable potential as a biomaterial, it has not been as thoroughly studied as its derivative chitosan. In this study, the potential of chitin gel beads has been evaluated for surface modification via vinyl polymer grafting. Grafting behavior of two well-established vinyl monomers, namely 2-hydroxyethylmethacrylate (HEMA) and 4-vinylpyridine (4-VP) were investigated using cerium (IV) ammonium nitrate as the redox initiator with the aim of obtaining chemically functionalized more hydrophilic chitin surfaces. The intractable nature of chitin, which is one of its primary drawbacks as a grafting substrate was overcome by applying a CaCO3 treatment during bead preparation. The maximum grafting percentage of poly(HEMA) onto chitin bead without CaCO3 treatment was found to be 65%, while the value for CaCO3 treated chitin beads was 515%. The maximum grafting yield of poly(4-VP) on to CaCO3 treated chitin powder was 380% at optimum conditions. The grafting system was extensively characterized before and after grafting by FT-IR, SEM, C-13 NMR and XRD analyses. Significant improvement on the swelling capacities of chitin based gel beads in aqueous acidic, basic and neutral media was obtained. An account of the pros and cons of the system has been presented.

Gene expression patterns associated with blood-feeding in the malaria mosquito Anopheles gambiae.

BACKGROUND: Blood feeding, or hematophagy, is a behavior exhibited by female mosquitoes required both for reproduction and for transmission of pathogens. We determined the expression patterns of 3,068 ESTs, representing ~2,000 unique gene transcripts using cDNA microarrays in adult female Anopheles gambiae at selected times during the first two days following blood ingestion, at 5 and 30 min during a 40 minute blood meal and at 0, 1, 3, 5, 12, 16, 24 and 48 hours after completion of the blood meal and compared their expression to transcript levels in mosquitoes with access only to a sugar solution. RESULTS: In blood-fed mosquitoes, 413 unique transcripts, approximately 25% of the total, were expressed at least two-fold above or below their levels in the sugar-fed mosquitoes, at one or more time points. These differentially expressed gene products were clustered using k-means clustering into Early Genes, Middle Genes, and Late Genes, containing 144, 130, and 139 unique transcripts, respectively. Several genes from each group were analyzed by quantitative real-time PCR in order to validate the microarray results. CONCLUSION: The expression patterns and annotation of the genes in these three groups (Early, Middle, and Late genes) are discussed in the context of female mosquitoes' physiological responses to blood feeding, including blood digestion, peritrophic matrix formation, egg development, and immunity.

Bacteriology of pressure ulcers in individuals with spinal cord injury: What we know and what we should know.

Individuals with spinal cord injury (SCI) are at increased risk for the development of pressure ulcers. These chronic wounds are debilitating and contribute to prolonged hospitalization and worse medical outcome. However, the species of bacteria and the role that specific species may play in delaying the healing of chronic pressure ulcers in the SCI population has not been well characterized. This study will review the literature regarding what is known currently about the bacteriology of pressure ulcers in individuals with SCI. An electronic literature search of MEDLINE (1966 to February 2014) was performed. Eleven studies detailing bacterial cultures of pressure ulcers in the SCI population met inclusion criteria and were selected for review. Among these studies, bacterial cultures were often polymicrobial with both aerobic and anaerobic bacteria identified with culture techniques that varied significantly. The most common organisms identified in pressure ulcers were Staphylococcus aureus, Proteus mirabilis, Pseudomonas aeruginosa, and Enterococcus faecalis. In general, wounds were poorly characterized with minimal to no physical description and/or location provided. Our present understanding of factors that may alter the microbiome of pressure ulcers in individuals with SCI is quite rudimentary, at best. Well-designed studies are needed to assess appropriate wound culture technique, the impact of bacterial composition on wound healing, development of infection, and the optimum medical and surgical approaches to wound care.