Valve-in-Valve Transcatheter Aortic Valve Replacement Versus Redo Surgical Aortic Valve Replacement In Patients With Aortic Stenosis: A Systematic Review and Meta-analysis.

Aortic stenosis is a common and significant valve condition requiring bioprosthetic heart valves (BHV) with transcatheter aortic valve replacement (TAVR) being strongly recommended for high-risk patients or patients over 75. This meta-analysis aimed to pool existing data on post-procedural clinical as well as echocardiographic outcomes comparing ViV-TAVR to redo-SAVR to assess the short-term and medium-term outcomes for both treatment modalities. A systematic literature search on Cochrane Central, Scopus, and Medline (PubMed interface) electronic databases from inception to August 2023. We used odds ratios (OR) for dichotomous outcomes and mean differences (MD) for continuous outcomes. Twenty-four studies (25,216 patients) were pooled with a mean follow-up of 16.4 months. The analysis revealed that ViV-TAVR group showed a significant reduction in 30-day mortality (OR: 0.50 (95% CI: 0.43, 0.58), P < 0.00001), new-onset atrial fibrillation (OR: 0.34 (95% CI: 0.17, 0.67) P = 0.002), major bleeding event (OR: 0.28 (95% CI: 0.17, 0.45), P < 0.00001) and lower rate of device success (OR: 0.25 (95% CI: 0.12, 0.53), P = 0.0003). There were no significant differences between either group when assessing 1-year mortality, stroke, M.I, post-operative LVEF, and effective orifice area. ViV-TAVR cohort showed a significantly increased incidence of paravalvular leaks, aortic regurgitation, and increased mean aortic valve gradient. ViV-TAVR is a viable short-term option for elderly patients with high comorbidities and operative risks, reducing perioperative complications and improving 30-day mortality with no significant cardiovascular adverse events. However, both treatment modalities present similar results on short to medium-term complications assessment.

Synthesis of new class of non-sulfonamide bis-benzimidazoles as antitumor agents by inhibiting carbonic anhydrase-IX enzyme.

In several types of cancers, the expression of carbonic anhydrase-IX (CA-IX) enzyme is elevated than its normal level which ultimately plays a key role in the tumor growth of epithelial cells in breast and lung cancer by acidifying tumor microenvironment, therefore, inhibition of this target is important in antitumor therapy. We have synthesized bis-benzimidazole derivatives (1-25) by using 3,3'-diaminobenzidine and various aromatic aldehydes and characterized by various spectroscopic methods (UV/Visible, 1HNMR, 13CNMR, and mass spectrometry). Their inhibitory potential for human CA-IX (hCA-IX) was evaluated in-vitro, where several synthesized derivatives showed potent inhibition of hCA-IX (IC50 values in range of 5.23 ± 1.05 to 40.10 ± 1.78 µM) and compounds 3-5, 7-8, 13-16, 21 and 23 showed superior activity than the standard drug "acetazolamide" (IC50 = 18.24 ± 1.43 µM). Furthermore, all these compounds showed no toxicity on human fibroblast cell lines (BJ cell lines). Moreover, molecular docking was carried out to predict their binding modes in the active site of CA-IX and revealed a significant role of imidazole ring of synthesized entities in their effective binding with the specific residues of CA-IX. The obtained results paved the way for further in vivo and other pharmacological studies for the optimization of these molecules as possible anti-cancer agents.

In vitro and in vivo antimicrobial potential of lithium complex against multi-drug resistant Acinetobacter baumannii.

IMPORTANCE: Multi-drug resistance (MDR) by virtue of evolving resistance and virulence mechanisms among A. baumannii is a global concern which is responsible for lethal hospital-acquired infections. Therefore, it is crucial to develop new therapeutics against it. Metal complexes are compact structures with diverse mechanisms that the pathogens cannot evade easily which make them a strong drug candidate. In this study, we assessed the in vitro and in vivo efficacy of lithium complex {[Li(phen)2 sal]} against biofilm-forming MDR A. baumannii. The lithium complex displayed strong antimicrobial activity and reduced the pre-formed mature biofilm which is key barrier for antimicrobial action. Moreover, it employs oxidative stress as one of its mode of actions and causes cellular rupturing. Lithium complex was non-toxic and was significantly effective to overcome pneumonia in mice model. These results highlight the untapped potential of metal complexes that can be explored and utilized for combating notorious A. baumannii infections.

Efficient Synthesis with Green Chemistry Approach of Novel Pharmacophores of Imidazole-Based Hybrids for Tumor Treatment: Mechanistic Insights from In Situ to In Silico.

Imidazole-based pyrimidine hybrids are considered a remarkable class of compounds in pharmaceutical chemistry. Here, we report the anticancer bioactivities of eleven imidazole-based pyrimidine hybrids (1-11) that specifically target cytosolic carbonic anhydrase (CAs) isoenzymes, including human CA-II and human CA-IX (hCA-II, and hCA-IX). A highly eco-friendly aqueous approach was used for the formation of a carbon-carbon bond by reacting aromatic nitro group substitution of nitroimidazoles with carbon nucleophiles. The in vitro results indicate that this new class of compounds (1-11) includes significant inhibitors of hCA IX with IC50 values in the range of 9.6 ± 0.2-32.2 ± 1.0 µM, while hCA II showed IC50 values in range of 11.6 ± 0.2-31.1 ± 1.3 µM. Compound 2 (IC50 = 12.3 ± 0.1 µM) showed selective inhibition for hCA-II while 7, 8, and 10 (IC50 = 9.6-32.2 µM) were selective for hCA-IX. The mechanism of action was investigated through in vitro kinetics studies that revealed that compounds 7, 3, 11, 10, 4, and 9 for CA-IX and 1, 2, and 11 for CA-II are competitive inhibitors with dissociation constant (Ki) in the range of 7.32-17.02 µM. Furthermore, the in situ cytotoxicity of these compounds was investigated in the human breast cancer cell line MDA-MB-231 and compared with the normal human breast cell line, MCF-10A. Compound 5 showed excellent anticancer/cytotoxic activity in MDA-MB-231 with no toxicity to the normal breast cells. In addition, in silico molecular docking was employed to predict the binding mechanism of active compounds with their targets. This in silico observation aligned with our experimental results. Our findings signify that imidazole-based hybrids could be a useful choice to design anticancer agents for breast and lung tumors, or antiglaucoma compounds, by specific inhibition of carbonic anhydrases.

Small and medium-sized enterprises failure in providing workers' rights concerning Sustainable Development Goals-2030 in Pakistan.

Small and medium-sized enterprises (SMEs) play an enormously crucial part in the modern world economy, demonstrating the most unique and incredible ground-breaking system. SMEs' employment statistics and future worker needs make it a focus of policies among rising economies, and Pakistan is no exception. The working conditions in SMEs diverge from industry to industry; however, irrespective of the industrial categorization, the SMEs are failing to protect the workers' rights in the perspective of Sustainable Development Goals (SDGs). The interpretivism paradigm and purposive sampling, narrative inquiry, and analysis method have been adopted to gain in-depth knowledge of workers' rights in SMEs concerning the SDGs. Results revealed that Pakistan-based SMEs argue to be financially weak and perceived as less equipped to adhere to the world's standards. Highlighted issues in failure to adhere to worker's rights include lack of financial resources, top management's commitment, regulatory framework, SDG awareness, strategic planning, and the dire need for expert guidance and consultation in translating goals to work environments.

Gigantic arteriovenous fistula between left coronary cusp and coronary sinus draining into the right atrium.

Coronary arteriovenous fistulas (CAF) are infrequent anatomic anomalies that establish a direct connection between coronary arteries and cardiac chambers. The reported incidence is extremely low and estimated at 0.002% in the general population. We report a rare case of CAF in a middle-aged man, who was asymptomatic but incidentally found to have a gigantic CAF on a low-dose Computed Tomography scan of his chest. The case was presented to cardiothoracic surgeons. Since the patient was asymptomatic, they recommended medical management and continued close surveillance. The Left Coronary Artery or its branches are extremely uncommon site for CAF. With the advances in technology, the network of veins including coronary sinus has gained further clinical relevance. While technology has helped elucidate many aspects of these rare anomalies, mysteries still remain. With continued research, we can expect more cost-effective and less invasive interventional therapies to be developed in the near future.

COVID-19 vaccination associated severe immune thrombocytopenia.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 has emerged as a deadliest global pandemic after its identification in December 2019 in Wuhan, China resulting in more than three million deaths worldwide. Recently FDA issued emergency authorization for three vaccines for prevention of COVID-19. Here in, we report three cases of severe immune thrombocytopenia (ITP) following COVID-19 vaccination and their clinical course. CASE PRESENTATIONS: Case #1: 53 year old male with past medical history of Crohn's disease was admitted for myalgias and diffuse petechial rash 8 days after receiving second dose of Pfizer-BioNTech COVID-19 vaccine. A complete blood test showed a platelet count of 2 × 109/L. Patient did not have a prior history of thrombocytopenia and other causes of thrombocytopenia were ruled out by history and pertinent lab data. He received two doses of intravenous immunoglobulin and oral dexamethasone for 4 days resulting in normalization of platelet counts. Case #2: 67 year male with past medical history of chronic ITP in remission was admitted for melena 2 days after receiving his first dose of Pfizer-BioNTech COVID-19 vaccine. A complete blood test showed a platelet count of 2 × 109/L. Physical exam showed generalized petechiae. There was no history of recent flares of ITP and patient had normal platelet counts following his splenectomy 4 years ago. He received two doses of IVIG and oral dexamethasone for 4 days with gradual improvement in platelet counts. Case #3: 59 year old female with past medical history of chronic ITP secondary to SLE was admitted for bloody diarrhea 2 days after receiving her first dose of Johnson and Johnson COVID-19 vaccine. Physical exam was unremarkable. A complete blood test showed platelet count of 64 × 109/L which dropped to 27 × 109/L during hospital course. She received oral dexamethasone for 4 days with improvement in platelet counts. CONCLUSION: COVID-19 vaccination induced ITP has been recently acknowledged. However, given very few cases and limited data, currently there are no guidelines for management of ITP caused by COVID-19 vaccine as well as vaccination of people with predisposing conditions.

Therapeutic potential of N4-substituted thiosemicarbazones as new urease inhibitors: Biochemical and in silico approach.

Urease enzyme plays a key role in pathogenesis of gastritis and peptic ulcers. Its inhibition averts our bodies from many disorders including formation of urinary calculi. In agriculture, the high urease content causes severe environmental and hence economic problems. Due to deficiency of effective and safer drugs to tackle the aforementioned disorders, the quest for new scaffolds becomes mandatory in the field of medicinal chemistry. In this regard, we herein report a new series of N4-substituted thiosemicarbazones 3a-v as potential candidates for urease inhibition. These new N4-substituted thiosemicarbazones 3a-v of distant chemical scaffolds were characterized by advanced spectroscopic techniques, such as FTIR, 1HNMR, 13CNMR, ESI-MS and in the case of compound 3g by single crystal X-ray analysis. The compounds were evaluated for their urease inhibitory potential. All newly synthesized compounds showed significant urease inhibitions with IC50 values in range of 2.7 ± 0.320-109.2 ± 3.217 µM. Molecular docking studies were used for interactions pattern and structure-activity relationship for all compounds, which demonstrated excellent binding interactions with the active site residues, such as hydrogen bonding, π-π interactions, π-H and nickel atom coordination.

Distal arteriovenous fistula formation after percutaneous coronary intervention: An old complication of a new access site.

Dorsal or distal transradial artery access has recently gained popularity due to several perceived benefits that include favorable ergonomics, the potential for rapid hemostasis and lower rates of vascular complications. Still, no vascular access site is free of complications and reports of hematoma and pseudoaneurysm formation related to distal radial artery access have been reported in the literature. We present a case of a 71-year-old male who developed an arteriovenous fistula (AVF) involving the distal left radial artery following repeated access of the artery. This rare complication is likely avoidable with a comprehensive understanding of the surrounding anatomy and proper procedural technique, including the routine use of ultrasound for access.

Complexes of N- and O-Donor Ligands as Potential Urease Inhibitors.

We report five new transition-metal complexes that inhibit the urease enzyme. Barbituric acid (BTA), thiobarbituric acid (TBA), isoniazid (INZ), and nicotinamide (NCA) ligands were employed in complexation reactions. The resulting complexes were characterized using a variety of analytical techniques including infra-red and UV-vis spectroscopy, 1H NMR spectroscopy, elemental analysis, and single-crystal X-ray diffraction analysis. We describe two mononuclear complexes with a general formula {[M(NCA)2(H2O)4](BTA)2(H2O)}, where M = Co (1) and Zn (2), a mononuclear complex {[Ni(NCA)2(H2O)4](TBA)2(H2O)} (3), and two polymeric chains of a general formula {[M(INZ) (H2O)3](BTA)2(H2O)3}, where M = Co (4) and Zn (5). These complexes displayed significant urease enzyme inhibition with IC50 values in the range of 3.9-19.9 µM.

Anti-tuberculous Effects of Statin Therapy: A Review of Literature.

Tuberculosis (TB) is a chronic infection caused by Mycobacterium tuberculosis (M. TB). It is transmitted through respiratory droplets. Increased cholesterol level is a predisposing factor for TB. M. TB uses cholesterol in the host macrophage membranes to bind and enter the macrophages. Statins are the drugs that are prescribed to hyperlipidemic patients to maintain their lipid levels in the normal range, thereby reducing the risk of stroke and cardiovascular events. Moreover, statins aid in reducing the levels of cholesterol in human macrophages. Therefore, a reduction in the membrane cholesterol minimizes the entry of TB pathogen inside macrophages. Furthermore, acting as vitamin D3 analogs and positively influencing pancreatic beta-cell function in a chronic diabetic state, statins minimize the occurrence of M. TB infection among diabetic population as well. This review aims to provide a comprehensive detail of all in vitro, in vivo, and retrospective studies that investigated the effects of statins in relation to the prevention or treatment of TB infection.

A highly green approach towards aromatic nitro group substitutions: catalyst free reactions of nitroimidazoles with carbon nucleophiles in water.

We have successfully developed a flexible green aqueous approach for the formation of a carbon-carbon bond by the reaction of highly-enolizable carbanions (mostly derived from 1,3-dicarbonyl compounds) with an aromatic carbon bearing a nitro group. The key step involves a nucleophilic displacement reaction. All newly synthesized compounds were unambiguously characterized via various spectroscopic techniques including NMR, mass spectrometry and single-crystal X-ray diffraction as applicable. We believe that our study will be useful in providing new insights into catalyst-free water-mediated nucleophilic substitution reactions.

Sodium, Potassium, and Lithium Complexes of Phenanthroline and Diclofenac: First Report on Anticancer Studies.

Diclofenac or 2-[(2',6'-dichlorophenyl)amino]phenyl}acetic acid (dcf) is a nonsteroidal anti-inflammatory drug, and 1,10-phenanthroline (phen) is a well-known enzyme inhibitor. In this study, three new alkali metal complexes (1-3) containing both phen and dcf were prepared, and their structures were characterized by a variety of analytical techniques including infrared and UV-vis spectroscopy, 1H NMR and 13C NMR elemental analysis, mass spectrometry, and single-crystal X-ray diffraction analysis. In these complexes, phen binds via a N,N'-chelate pocket, while the monoanionic dcf-ligand remains either uncoordinated (in the case of 1 and 3) or coordinated in a bidentate fashion (in the case of 2). All three complexes crystallize in the triclinic space group P-1. [Na2(phen)2 (H2O)4][dcf]2 (1) is a dinuclear sodium complex, where two crystallographically identical Na+ cations adopt a distorted five-coordinate spherical square-pyramidal geometry, with a [N2O3] donor set. [K2(phen)2(dcf)2(H2O)4] (2) is also a dinuclear complex where the crystallographically unique K+ cation adopts a distorted seven-coordinate geometry comprising a [N2O5] donor set. [Li(phen)(H2O)2][dcf] (3) is a mononuclear lithium complex where the Li+ cation adopts a four-coordinate distorted tetrahedral geometry comprising a [N2O2] donor set. The complexes were evaluated for their anticancer activity against lung and oral cancer cell lines as well as for their antibacterial potential. The prepared complexes displayed very good antibacterial and anticancer activities with an excellent bioavailability.

Obesity And Diabetes As Determinants Of Vitamin D Deficiency.

BACKGROUND: Vitamin D has been the focus of attention in the recent past owing to its multitude of effects on various organ systems including immune system, endocrine, cardiovascular etc. Diabetes mellitus and obesity are widely prevalent in our region. The present study was designed with an objective to determine the vitamin D status in relation to diabetes mellitus and obesity in our area. METHODS: This cross-sectional study was conducted at the Medical C Unit of Department of Medicine, Ayub Teaching Hospital from January to December 2017. Approval of ethical committee was taken. A total of 117 patients were enrolled in this study of which 109 were finalized for analysis owing to incomplete data in 8 cases. Patients' characteristics were recorded on a structured proforma. Type 2 diabetes was confirmed using HbA1C Levels. Using ADA 2016 criteria. Vitamin D status was assessed using 25-OH-Vit D levels from the same laboratory. Height and weight of the patients were recorded to obtain BMI. Data was entered and analysed using SPSS version 20. RESULTS: Of the total sample, 69 (63.3%) were females and 40 (36.7%) were males. Mean age of the participants was 44.13±15.777. Mean vitamin D levels were 26.35±18.72. A total of 83 (76.14%) patients were either vitamin D deficient 66 (60.6%) or insufficient 17 (15.6%) while 26 (23.9%) were sufficient in vitamin D. There was statistically significant difference in vitamin D status in diabetic versus non diabetic patients (p=0.015). As regards BMI and vitamin D status, the difference was also statistically significant (p=0.018). CONCLUSIONS: Vitamin D deficiency is widely prevalent in our region. There is also a high prevalence of obesity and diabetes mellitus and they are inversely related to low vitamin D levels.

Crystal structure, shape analysis and bioactivity of new LiI, NaI and MgII complexes with 1,10-phenanthroline and 2-(3,4-dichlorophenyl)acetic acid.

Reactions of 1,10-phenanthroline (phen) and 2-(3,4-dichlorophenyl)acetic acid (dcaH) with Mn(CO3) (M = LiI, NaI and MgII; n = 1 and 2) in MeOH yield the mononuclear lithium complex aqua[2-(3,4-dichlorophenyl)acetato-κO](1,10-phenanthroline-κ2N,N')lithium(I), [Li(C8H5Cl2O2)(C12H8N2)(H2O)] or [Li(dca)(phen)(H2O)] (1), the dinuclear sodium complex di-µ-aqua-bis{[2-(3,4-dichlorophenyl)acetato-κO](1,10-phenanthroline-κ2N,N')sodium(I)}, [Na2(C8H5Cl2O2)2(C12H8N2)2(H2O)2] or [Na2(dca)2(phen)2(H2O)2] (2), and the one-dimensional chain magnesium complex catena-poly[[[diaqua(1,10-phenanthroline-κ2N,N')magnesium]-µ-2-(3,4-dichlorophenyl)acetato-κ2O:O'] 2-(3,4-dichlorophenyl)acetate monohydrate], {[Mg(C8H5Cl2O2)(C12H8N2)(H2O)2](C8H5Cl2O2)·H2O}n or {[Mg(dca)(phen)(H2O)2](dca)·H2O}n (3). In these complexes, phen binds via an N,N'-chelate pocket, while the deprotonated dca- ligands coordinate either in a monodentate (in 1 and 2) or bidentate (in 3) fashion. The remaining coordination sites around the metal ions are occupied by water molecules in all three complexes. Complex 1 crystallizes in the triclinic space group P-1 with one molecule in the asymmetric unit. The Li+ ion adopts a four-coordinated distorted seesaw geometry comprising an [N2O2] donor set. Complex 2 crystallizes in the triclinic space group P-1 with half a molecule in the asymmetric unit, in which the Na+ ion adopts a five-coordinated distorted spherical square-pyramidal geometry, with an [N2O3] donor set. Complex 3 crystallizes in the orthorhombic space group P212121, with one Mg2+ ion, one phen ligand, two dca- ligands and three water molecules in the asymmetric unit. Both dcaH ligands are deprotonated, however, one dca- anion is not coordinated, whereas the second dca- anion coordinates in a bidentate fashion bridging two Mg2+ ions, resulting in a one-dimensional chain structure for 3. The Mg2+ ion adopts a distorted octahedral geometry, with an [N2O4] donor set. Complexes 1-3 were evaluated against urease and α-glucosidase enzymes for their inhibition potential and were found to be inactive.

Desensitization therapy using 'Mariana Castells' protocol in a patient with multiple autoimmune disorders- does it work?

Clinical use of antibiotics is becoming more widespread with each passing day for various infectious diseases. This has caused an abrupt increase in hypersensitivity reactions linked to these drugs, sometimes preventing the use of first-line therapies. In these patients, clinical presentation may vary from mild skin infections to life-threatening anaphylactic reactions. Our patient is a 30 year old female with past medical history significant for mast cell activation syndrome and multiple autoimmune diseases who presented with chief complaint of fever. Patient was diagnosed with MSSA bacteremia requiring the start of an antibiotic regimen. Mariana castells protocol was used for desensitizing the patient before starting her on antibiotic regimen. Patient was desensitized in 2 days using the standard 12-step protocol and started on cefazolin for her long-term treatment of the infection. No acute episodes of drug hypersensitivity were reported. During the course of her hospital admission, she improved significantly with no complications. Our patient having a history of both multiple autoimmune diseases and mast-cell activation syndrome tolerated the protocol well with no complications. Appropriate treatment of the reactions including epinephrine use and management with personalized desensitization protocols can enhance the quality of life, life expectancy, and safety of an increasing at risk population of patients with infectious diseases allergic to their best medications. Protocols, such as mariana castells, are completely safe in autoimmune disorders and should be utilized as the standard of care in appropriate patient population.