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.

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.

Antimicrobial Resistance Patterns In Community Acquired Urinary Tract Infections.

BACKGROUND: Urinary tract infection (UTI) is the most frequent disease for which patients seek medical care. The antimicrobial agents causing UTI and their sensitivity patterns have remarkably changed throughout the world over the past few years. Hence, the present study was designed to explore the uropathogens and their susceptibility to various molecules in our region. METHODS: This descriptive cross sectional study was conducted at Medical C Unit of Ayub Teaching Hospital, Abbottabad from January 2015 to January 2016. Patients with clinical features of UTI were evaluated using Urine R/E and Urine culture and sensitivity. Ten antibiotics were checked for susceptibility. Results were analysed using SPSS 17. RESULTS: A total of 630 patients presented with urinary complaints. Of these, 236 patients had more than 8-10 pus cells on urine R/E. They were further evaluated using culture and sensitivity and positive culture was obtained in 75 patients. Of these 34 (45.3%) were males and 41 (54.7%) were females. E Coli was the predominant isolate being present in 49 (65.3%) patients. This was followed by Klebsiella in 9 (12%) patients. Tazobactam-piperacillin and cefoperazone-sulbactam were the most sensitive drugs having overall sensitivity of 96% and 93.3% respectively. The isolates were highly resistant to Fluoroquinolones 77.3% followed by Penicillins 72% and TMP-SMX 69.3%. CONCLUSIONS: Antibiotic sensitivity patterns have enormously changed over the past decade. Newer agents are quite efficacious but their use should be highly judicious to prevent the development of resistance to these molecules.

Risk assessment for obstructive sleep apnea and anxiety in a Pakistani population with coronary artery disease.

PURPOSE: Previous studies in the western world have reported the possible association of obstructive sleep apnea (OSA) with anxiety and cardiovascular diseases. However, the data from developing countries such as Pakistan remains scarce in this regard. The main aim of this study was to investigate the prevalence of coronary artery disease (CAD) patients who are at high risk of OSA and to determine the association between the risk of OSA and levels of anxiety. METHODS: The sample population consisted of 400 participants including 200 patients, who had been previously diagnosed with CAD, and 200 healthy controls. The 200 CAD patients were approached for inclusion in the study on their follow-ups after their acute symptoms had subsided. The patients were interviewed after a mean time period of 13 weeks post event. All patients with lung disease or respiratory infection were excluded from the study. The risk of OSA was determined using Berlin questionnaire, while the levels of anxiety were measured by Beck anxiety inventory scale (BAI). RESULTS: More than half (n = 104) of the CAD patients were at high risk of OSA while majority (n = 168) of the healthy controls were at low risk. The high risk of OSA was significantly (P < 0.0001) more prevalent in CAD patients compared with controls. It was also observed that the patients who were at high risk of OSA, among both cases and controls, had significantly (P values <0.001) higher levels of anxiety. CONCLUSION: A significant proportion of CAD patients are at high risk of OSA in our region. Moreover, OSA is also associated with greater levels of anxiety in both healthy people and CAD patients.

FREQUENCY OF HOSPITAL ACQUIRED HYPONATREMIA IN A PEDIATRIC TERTIARY CARE SETTING.

BACKGROUND: Hyponatremia is the most commonly encountered electrolyte disorder in children. In our country the epidemiology of hospital acquired hyponatremia has hardly ever been explored whereas the administration of hypotonic IV fluids is widely practiced here. Therefore we pioneered to conduct this study to determine the frequency of hospital acquired hyponatremia. METHODS: This was a cross sectional study carried out at Aga Khan University Hospital, Karachi in paediatric ward and ICU over a period of 12 months. All children (>1 month and <15 years of age) admitted in paediatric units and on maintenance IV fluids who had serum sodium level measured on admission were included in the study and followed to identify patients who had a drop in serum sodium during hospitalization. Informed consent was taken from parents and collected data was recorded on a pro forma. RESULTS: A total of 865 patients were enrolled in the study. Hyponatremia was recorded in 405 patients on admission (46.8%) while hospital acquired hyponatremia was documented in 240. children (27.7%). Out of these 142 (59.2%) were male and 98 (40.8%) were female. Mean age of children in hospital acquired hyponatremia group was 60.67 months. Severity of hospital acquired hyponatremia was recorded as mild in 191 (79.6%), moderate in 35 (14.6%) and severe in 14 (5.8%) children. Major disease categories included gastrointestinal disorder (30.4 %), respiratory illness (12.5%), oncological disease (16.3%), cardiovascular disease (11.7%), infectious disease (9.2%) and neurological illness (8.3%). CONCLUSION: Hospital acquired hyponatremia is frequently encountered in our hospitalized children with majority of them receiving hypotonic IV solutions.

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.

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 with transcatheter aortic valve replacement (TAVR) being strongly recommended for high-risk patients or patients over 75 years. This meta-analysis aimed to pool existing data on postprocedural clinical as well as echocardiographic outcomes comparing valve-in-valve (ViV)-TAVR to redo-surgical aortic valve replacement to assess the short-term and medium-term outcomes for both treatment methods. 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% confidence interval [CI] 0.43 to 0.58, p <0.00001), new-onset atrial fibrillation (OR 0.34, 95% CI 0.17 to 0.67, p = 0.002), major bleeding event (OR 0.28, 95% CI 0.17 to 0.45, p <0.00001) and lower rate of device success (OR 0.25, 95% CI 0.12 to 0.53, p = 0.0003). There were no significant differences between either group when assessing 1-year mortality, stroke, myocardial infarction, postoperative left ventricular ejection fraction, 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 older patients with high co-morbidities and operative risks, reducing perioperative complications and improving 30-day mortality with no significant cardiovascular adverse events. However, both treatment methods present similar results on short-term to medium-term complications assessment.

Comparison of knowledge, attitude and practices of betelnut users in two socio-economic areas of Karachi.

OBJECTIVE: To gain an insight on the knowledge, attitude and practices of those who chew betel nut in two different socioeconomic regions of Karachi. METHODS: The cross-sectional study was conducted in Saddar and Defence areas of Karachi over a five-week period in March-April 2012. Individual interviews following verbal consent were conducted using a pre-coded questionnaire, which was divided into 3 sections to analyse the knowledge, attitude and practices of the chewers. The data was entered and analysed using SPSS v. 16.0. Pearson's chi-square was used as the primary statistical test. RESULTS: A total of 370 subjects, 185 (50%) from each area, comprised the study. Majority of the chewers in Defence had higher educational qualification and income. Most of the participants in both areas acknowledged that betel nut chewing can potentially result in mouth (n = 274; 74.1%) and throat cancers (n = 267; 72.2%). A large part of the sample (n = 299; 80.8%) conceded that betel nut chewing is a bad habit, and almost half the sample was addicted to it (n = 194; 52.4%). CONCLUSION: Awareness regarding the detrimental effects of betel nut was satisfactory amongst the subjects, but the population was not willing to quit the habit. We recommend a two-pronged approach, offering widespread educational and awareness campaigns to prevent increased consumption of betel nuts, and professional counselling services for those already addicted.

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.

Caffeine-N-phthaloyl-ß-alanine (1/1).

The title co-crystal [systematic name: 3-(1,3-dioxoisoindolin-2-yl)propanoic acid-1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione (1/1)], C(8)H(10)N(4)O(2)·C(11)H(9)NO(4), is the combination of 1:1 adduct of N-phthaloyl-ß-alanine with caffeine. The phthalimide and purine rings in the N-phthaloyl-ß-alanine and caffeine mol-ecules are essentially planar, with r.m.s. deviations of the fitted atoms of 0.0078 and 0.0118 Å, respectively. In the crystal, the two mol-ecules are linked via an O-H⋯N hydrogen bond involving the intact carb-oxy-lic acid (COOH) group. The crystal structure is consolidated by C-H⋯O inter-actions. The H atoms of a methyl group of the caffeine mol-ecule are disordered over two sets of sites of equal occupancy.

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.

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.

The 1:1 adduct of caffeine and 2-(1,3-dioxoisoindolin-2-yl)acetic acid.

IN THE CRYSTAL STRUCTURE OF THE TITLE ADDUCT [SYSTEMATIC NAME: 2-(1,3-dioxoisoindolin-2-yl)acetic acid-1,3,7-trimethyl-1,2,3,6-tetra-hydro-7H-purine-2,6-dione (1/1)], C(8)H(10)N(4)O(2)·C(10)H(7)NO(4), the components are linked by an O-H⋯N hydrogen-bond and no proton transfer occurs.

catena-Poly[[diaqua-calcium]bis-[µ-2-(1,3-dioxoisoindolin-2-yl)acetato]-κO,O':O;κO:O,O'].

In the title complex, [Ca(C(10)H(6)NO(4))(2)(H(2)O)(2)](n), the Ca(II) atom lies on a twofold rotation axis and adopts a dodeca-hedral geometry. The Ca(II) atom is octa-coordinated by two O atoms from two water mol-ecules and six O atoms from four acetate ligands. Each acetate acts as a tridentate ligand bridging two Ca(II) atoms, resulting in a chain running along the c axis. O-H⋯O and C-H⋯O hydrogen bonds connect the chains into a two-dimensional network parallel to [011]. π-π inter-actions between adjacent isoindoline-1,3-dione rings [centroid-centroid distance = 3.4096 (11) Å] further consolidate the structure. One of the carboxylate O atoms is disordered over two sites in a 0.879 (12):0.121 (12) ratio.

Aetiological profile of acquired anaemia in a paediatric tertiary care setting.

BACKGROUND: Anaemia is the commonest haematological disorder frequently faced by clinicians worldwide. The multi-factorial aetiology of the disorder warrants a comprehensive search for the different causes as management plans differ for different disorders. The objective of this study was to identify the different acquired causes of anaemia in our paediatric population. METHODS: The study was conducted at the Department of Paediatrics, Ayub Teaching Hospital from April 2009 to April 2010. It was a cross-sectional study. A total of 110 patients were included in the study who presented with anaemia secondary to acquired aetiologies and were assessed clinically using general physical and systemic examination. The salient clinical and laboratory data was retrieved in designed protocol. RESULTS: Out of a total of 110 patients, 61 (55.5%) were male and 49 (44.5%) were female. Mean age of the participants was 48 months. Nutritional anaemia comprising iron deficiency anaemia and megaloblastic anaemia was the leading cause being present in 49 (44.5%) patients followed by Visceral Leishmaniasis in 28 (25.5%) patients. Mean haemoglobin was 4.36 g/dl. CONCLUSION: Anaemia secondary to acquired causes is a disorder with grave consequences ranging from cognitive and psychomotor dysfunction to mortality in severe cases. Identification of the different acquired causes is important in preventing the disorder by guiding appropriate interventions.

Childhood strokes: epidemiology, clinical features and risk factors.

BACKGROUND: Stroke constitutes a significant health problem in paediatric population. The impact of childhood stroke can easily be realised in terms of economic, social and psychological burden related to disability of the affected children. The objective of study was to outline the epidemiology and clinical features of stroke in a cohort of Pakistani children and also ascertain the causes and potential risk factors in these patients. METHODS: The study was conducted at the Department of Paediatrics, Ayub Teaching Hospital from January 2008 to October 2010. It was a cross sectional study. A total of 46 patients were included in the study who presented with cerebrovascular disease and were assessed clinically using general physical and systemic examination. The salient epidemiological, clinical, neuro-imaging and laboratory data was retrieved in designed protocol. RESULTS: Out of a total of 46 patients, 50% were from either gender. Mean age of presentation was 39 months. Limb weakness was the commonest presenting feature being present in 37 (80.43%) patients. Infectious disorders was the most prevalent risk factor present in 31 (67.39%) patients followed by microcytic hypochromic anaemia in 28 (60.86%) patients. CONCLUSION: A Childhood stroke is a disorder with long term morbidity. Identification of risk factors is important in preventing the disorder by guiding appropriate interventions.

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.

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.

Gender differences of dyslipidemia in type 2 diabetics.

BACKGROUND: Type II diabetic patients are at an increased risk of coronary artery disease and cerebrovascular disease because of deranged lipid metabolism. Female diabetic patients are predominantly at risk. The objective of this cross-sectional study was to determine effects of gender on dyslipidemia of type II diabetic patients. METHODS: This study was carried out at Out-Patients Department, Medical A Unit, Ayub Teaching Hospital Abbottabad from 27th May to 27th November 2009. All type II diabetic patients who were above 40 and gave consent were included in the study. Data was collected through a structured proforma. Pattern of dyslipidemia in type II diabetic patients were estimated by computing all the four types of dyslipidemia like hypertriglyceridemia, low HDL, increased serum total cholesterol and increased serum LDL. RESULTS: There were 150 patients with mean age 65.67 +/- 11.29 years. There were 80 (53.33%) male and 70 (46.7%) female patients. Mean BMI was 28.45 +/- 3.30 Kg/m2. Mean serum cholesterol level was 3.9 +/- 1.31 mmol/L, triglyceride level was 2.98 +/- 1.14 mmol/L, LDL level was 3.28 +/- 0.85 mmol/L and HDL was 0.95 +/- 0.02 mmol/L. Women were more frequent to have low level HDL as compare to men (p < 0.05), while no significant difference was found regarding serum cholesterol, serum triglyceride and serum LDL (p > 0.05). CONCLUSION: Female diabetic patients have increased frequency of low level of serum HDL as compared to males.

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.