Metallaaromaticity - a protean world.

The nature of magnetically induced current densities (MICD) of metallabenzenes and related compounds has been examined with relativistic DFT calculations to assess the magnetic aromaticity of the molecules. The origin of the total MICD has been analyzed in terms of individual molecular orbital (MO) contributions. Our study reveals that the σ-framework of the molecules always makes a diamagnetic contribution to the MICD. On the other hand, π-MOs and Craig-Möbius type π-MOs, i.e., MOs in which the dxy/dxz orbitals of the metal centers change the phase of the wave function akin to a Möbius twist, may not make a diatropic contribution. We have identified metallabenzenes with multiple magnetic aromaticities. In the case of iridabenzenes, σ-MICD has been found to decrease dramatically from Ir(III) to Ir(V) systems. Furthermore, a brief examination of some recently synthesized metallapolycycles has shown that the metal center in a given ring can strongly modulate the aromaticity of neighboring rings. Finally, the finding that relatively minor perturbations in the ligand environment of the metal can substantially influence the aromaticity of metallabenzenes and related molecules underscores the protean character of metallaaromaticity and the need for even wider-ranging investigations. Considering the conflicts between magnetic response and ground-state aromaticity criteria (energetic, structural, and electronic criteria), we propose that the term aromatic be used for labeling a molecule if and only if all criteria confirm aromaticity. In other words, neither magnetic nor ground-state criteria are necessary and sufficient conditions for labeling a molecule aromatic.

Relativistic Spin-Orbit Electronegativity and the Chemical Bond Between a Heavy Atom and a Light Atom.

Radek Marek and his co-workers at Masaryk University, Brno, Czechia have been invited to prepare the cover of this issue. The image depicts the relativistic spin-orbit coupling that is associated with the presence of a heavy atom in a molecule influencing the electron density around a light atom and modulating the chemical bond between these two atoms. Read the full text of the article at 10.1002/chem.202200277.

Relativistic Spin-Orbit Electronegativity and the Chemical Bond Between a Heavy Atom and a Light Atom.

Relativistic effects are known to alter the chemical bonds and spectroscopic properties of heavy-element compounds. In this work, we introduce the concept of spin-orbit (SO) electronegativity of a heavy atom, as reflected by an SO-induced change in the interatomic distance between the heavy atom (HA) and a neighboring light atom (LA). We provide a transparent interpretation of these SO effects by using the concept of spin-orbit electron deformation density (SO-EDD). Spin-orbit coupling at the HA induces rearrangement of the electron density for the scalar-relativistically optimized geometry that, in turn, exerts a new force on the LA. The resulting expansion or contraction of the HA-LA bond depends on the nature and electron configuration of the HA. In addition, we quantify the change in atomic electronegativity induced by SO coupling for a series of hydrides, thereby complementing the SO-EDD picture. The trends in the SO-induced electronegativity and the HA-LA bond length across the periodic table of elements are demonstrated and interpreted, and also linked, intuitively, with the SO-induced NMR shielding at the LA.

Supramolecular Coronation of Platinum(II) Complexes by Macrocycles: Structure, Relativistic DFT Calculations, and Biological Effects.

Platinum-based anticancer drugs are actively developed utilizing lipophilic ligands or drug carriers for the efficient penetration of biomembranes, reduction of side effects, and tumor targeting. We report the development of a supramolecular host-guest system built on cationic platinum(II) compounds bearing ligands anchored in the cavity of the macrocyclic host. The host-guest binding and hydrolysis process on the platinum core were investigated in detail by using NMR, MS, X-ray diffraction, and relativistic DFT calculations. The encapsulation process in cucurbit[7]uril unequivocally promotes the stability of hydrolyzed dicationic cis-[PtII(NH3)2(H2O)(NH2-R)]2+ compared to its trans isomer. Biological screening on the ovarian cancer lines A2780 and A2780/CP shows time-dependent toxicity. Notably, the reported complex and its ß-cyclodextrin (ß-CD) assembly achieve the same cellular uptake as cisplatin and cisplatin@ß-CD, respectively, while maintaining a significantly lower toxicity profile.

Anatomy of Base Pairing in DNA by Interacting Quantum Atoms.

The formation of purine and pyrimidine base pairs (BPs), which contributes to shaping of the canonical and noncanonical 3D structures of nucleic acids, is one the most investigated phenomena in chemistry and life sciences. In this contribution, the anatomy of the bond energy (BDE) of the base-pairing interaction in 39 different arrangements found experimentally or predicted for DNA structures containing the four common nucleobases (A, C, G, T) in their neutral or protonated forms is described in light of the theory of interacting quantum atoms within the context of the quantum theory of atoms in molecules. The interplay of individual energy components involved in the three stages of the bond formation process (structural deformation, electron-density promotion, and intermolecular interaction) is studied. We recognized that for the neutral BPs, variations in the kinetic and electrostatic contributions to the BDE are rather negligible, leaving the exchange-correlation energy as the main stabilizing component. It is shown that the contribution of the exchange-correlation term can be recovered by including atoms that are formally assumed to be hydrogen bonded (primary interaction). In contrast, to recover the electrostatic component of interaction, one must consider both the primary and secondary (formally nonbonded atoms) interatomic interactions. The results of our study were employed to design new types of BPs with altered bonding anatomy. We demonstrate that improving the electrostatic characteristics of the BPs does not necessarily result in greater interaction energies if weak secondary hydrogen bonding is destroyed. However, the main tuning factor for systems with conserved interacting faces (primary interactions) is the electrostatic component of the interaction energy resulting from the secondary atom-atom electrostatics.

Health care utilization and costs by metabolic syndrome risk factors.

BACKGROUND: This study compared prevalent health utilization and costs for persons with and without metabolic syndrome and investigated the independent associations of the various factors that make up metabolic syndrome. METHODS: Subjects were enrollees of three health plans who had all clinical measurements (blood pressure, fasting plasma glucose, body mass index, triglycerides, and high-density lipoprotein cholesterol) necessary to determine metabolic syndrome risk factors over the 2-year study period (n = 170,648). We used clinical values, International Classification of Diseases, Ninth Revision (ICD-9) diagnoses, and medication dispensings to identify risk factors. We report unadjusted mean annual utilization and modeled mean annual costs adjusting for age, sex, and co-morbidity. RESULTS: Subjects with metabolic syndrome (n = 98,091) had higher utilization and costs compared to subjects with no metabolic syndrome (n = 72,557) overall, and when stratified by diabetes (P < 0.001). Average annual total costs between subjects with metabolic syndrome versus no metabolic syndrome differed by a magnitude of 1.6 overall ($5,732 vs. $3,581), and a magnitude of 1.3 when stratified by diabetes (diabetes, $7,896 vs. $6,038; no diabetes, $4,476 vs. $3,422). Overall, total costs increased by an average of 24% per additional risk factor (P < 0.001). Costs and utilization differed by risk factor clusters, but the more prevalent clusters were not necessarily the most costly. Costs for subjects with diabetes plus weight risk, dyslipidemia, and hypertension were almost double the costs for subjects with prediabetes plus similar risk factors ($8,067 vs. $4,638). CONCLUSIONS: Metabolic syndrome, number of risk factors, and specific combinations of risk factors are markers for high utilization and costs among patients receiving medical care. Diabetes and certain risk clusters are major drivers of utilization and costs.

Development of a Scale for Evaluation of Tomato yellow leaf curl virus Resistance Level in Tomato Plants.

ABSTRACT We have developed a scale of differential hosts that enables the determination and comparison of level of resistance to Tomato yellow leaf curl virus (TYLCV) expressed by resistant tomato lines or by individual plants in a segregating population. The scale is composed of seven different homozygous tomato genotypes that exhibit different levels of TYLCV resistance, ranging from fully susceptible to highly resistant. The differential hosts composing the scale were inoculated with TYLCV under greenhouse conditions. Four weeks after inoculation the plants were evaluated for disease symptom severity, and virus DNA titer was determined. The different genotypes were arranged in the scale according to symptom severity score. The different genotypes were then tested under different environmental conditions, inoculated at different ages, and tested in a field experiment assaying TYLCV-induced yield reduction. While the symptom severity score of each individual resistant genotype changed under different environmental conditions, the relative position on the scale did not alter, except for one genotype. Thus, to evaluate disease resistance of a given tomato genotype, the genotype in question should be inoculated alongside the differential hosts composing the scale, and within 4 weeks one can determine the relative level of resistance of the tested genotype.

Capsicum Species: Symptomless Hosts and Reservoirs of Tomato yellow leaf curl virus.

ABSTRACT Five Capsicum species were tested for susceptibility to Tomato yellow leaf curl virus (TYLCV) and the mild strain of TYLCV (TYLCV-Mld). TYLCV was able to infect 30 of 55 genotypes of C. annuum, one of six genotypes of C. chinense, one of two genotypes of C. baccatum, and the only genotype of C. frutescens tested but was unable to infect the one genotype of C. pubescens tested. This is the first evidence for the susceptibility of C. baccatum, C. chinense, and C. frutescens to TYLCV. Unlike TYLCV isolates, TYLCV-Mld was unable to infect C. chinense. No host differences were observed between the Israeli and Florida isolates of TYLCV. None of the Capsicum species showed symptoms after infection with TYLCV or TYLCV-Mld. TYLCV was detected in fruits of C. annuum, but whiteflies were unable to transmit virus from fruits to plants. White-flies were able to transmit both TYLCV and TYLCV-Mld from infected pepper plants to tomato plants. Pepper plants in research plots were found infected with TYLCV at rates as much as 100%. These data demonstrate the ability of some genotypes of pepper to serve as reservoirs for the acquisition and transmission of TYLCV and TYLCV-Mld.

Persistent asthma: disease control, resource utilisation and direct costs.

Despite evidence that adverse outcomes are less frequent when asthma management is optimised, the link between the level of control, disease severity and medical resource utilisation (MRU) is poorly documented. This relationship was investigated in a group of patients suffering from persistent asthma (Global Initiative for Asthma (GINA) > or = 2) in France. In 1998 a computerised family practice database was used to identify asthma patients aged 17-50 yrs. Information from the database was complemented by a patient survey to retrospectively assess the level of asthma control and hospital contacts. Costs of MRU over a 12-month study period were related to demographics, medical history, asthma control, and doses of inhaled corticosteroids prescribed during the prestudy period. A review of the computerised medical database identified 1,038 adult patients with persistent asthma, who completed the survey questionnaire. Over a 12-month period, the mean cost of MRU was 549.8 euros for well-controlled patients, 746.3 euros per patient with moderate control, and 1,451.3 euros per patient with poor control. Costs also increased significantly with age, access to free asthma care, comorbid conditions, asthma symptoms in the past year and whether inhaled corticosteroids had been prescribed before the study period. In patients with persistent asthma, large differences were observed in the use of medical resources according to control and severity. Therefore, if patients appropriately use prescribed control therapy, their use of medical resources may be reduced.

Inpatient resource utilisation in younger (2-5 yrs) and older (6-14 yrs) asthmatic children in Finland.

Asthma is the most common chronic disorder among Finnish children, however, the economic burden of paediatric asthma in Finland has not yet been comprehensively evaluated. The objective of this study was to compare inpatient resource utilisation between younger (2-5 yrs) and older children (6-14 yrs) with asthma in Finland. A national database of inpatient resource utilisation was applied to determine use of hospital services among children with asthma in 1999. Regional estimates of charges were combined with hospitalisation episodes to determine total inpatient cost. The results indicate that younger asthmatic children consume 3-times more inpatient resources per capita. Incidence of first admissions because of asthma was 3-times higher in younger children. Hospitalisation and rehospitalisation rates were also 3- and 4-times higher, respectively. The total annual inpatient cost of asthma in children aged 2-5 and 6-14 yrs was Euro 1.98 million with each group accounting for Euro 1.12 million and Euro 0.86 million, respectively. Regional and age-related differences in hospitalisation rates and costs were likely related to variable clinical practice on the primary level, difficulties with diagnosis and compliance among younger children.

Changes in asthma drug therapy costs for patients receiving chronic montelukast therapy in the U.K.

The aim of this study was to assess changes in the costs of asthma drug therapy before and during the use of chronic montelukast treatment in the U.K. A retrospective cohort analysis of a primary care database in the U.K. was carried out. Patients with chronic montelukast use (> or = 140 once-daily doses) were selected for analysis. Benchmarking data were obtained for matched patients with chronic inhaled corticosteroid (ICS) use and patients with chronic salmeterol therapy with concomitant ICS use. The main outcome measures were changes in utilization and monthly cost of asthma therapies costs. Asthma patients experienced significant (P<0.05) reductions in the monthly costs of ICS, short-acting beta-agonists and antibiotics following chronic montelukast therapy. Monthly concomitant drug costs were reduced by Pound Sterling 7.49 per month, which offset 27.5% of the additional cost of montelukast, yielding an increase in total drug costs of Pound Sterling 19.78 per month. Meanwhile, increased total drug costs for matched patients with chronic ICS use, and matched patients with chronic salmeterol therapy and concomitant ICS use, increased by Pound Sterling 5.37 per month and Pound Sterling 44.55 per month respectively. Additionally, patients using chronic montelukast therapy experienced a statistically significant (P<0.05) reduction in the use of short acting beta-agonists, and antibiotics, suggesting improvement in asthma control. Chronic use of montelukast therapy is associated with a reduction of concomitant drug therapy costs.

Effect of Host Plant Resistance to Tomato yellow leaf curl virus (TYLCV) on Virus Acquisition and Transmission by Its Whitefly Vector.

ABSTRACT The effect that Tomato yellow leaf curl virus (TYLCV)-infected resistant tomato plants may have on virus epidemiology was studied. Four tomato genotypes that exhibit different levels of viral resistance, ranging from fully susceptible to highly resistant, served as TYLCV-infected source plants. Viral acquisition and transmission rates by white-flies following feeding on the different source plants were evaluated. TYLCV transmission rate by whiteflies that had fed on infected source plants 21 days postinoculation (DPI), shortly after the appearance of TYLCV symptoms, was negatively correlated with the level of resistance displayed by the source plant. Therefore, the higher the resistance, the lower the transmission rate. In addition, TYLCV DNA accumulation was shown to be lower in the resistant source plants compared with the susceptible plants. Whitefly survival rate, following feeding on source plants 21 DPI, was similar for all the cultivars tested. Significant differences in whitefly survival were found, however, following feeding on the infected source plants at 35 DPI; here, whitefly survival rate increased with higher levels of resistance displayed by the source plant. At 35 DPI, the susceptible plants had developed severe TYLCV disease symptoms, and transmission rates from these plants were the lowest, presumably due to the poor condition of these plants. Transmission rates from source plants displaying a medium level of resistance level were highest, with rates declining following feeding on source plants displaying higher levels of TYLCV resistance. TYLCV DNA accumulation in whiteflies following feeding on infected source plants at both 21 and 35 DPI was directly correlated with viral DNA accumulation in source plants. Results show that, in essence, the higher the resistance expressed, the less suitable the plant was as a viral source. Consequently, following acquisition from a highly resistant plant, TYLCV transmission by whiteflies will be less efficient.

The relationship between prescribed and delivered doses of inhaled corticosteroids in adult asthmatics.

A model was developed to estimate the impact of adherence and inhalation technique over time on delivered doses of inhaled corticosteroids (ICS) for asthmatics using metered-dose inhalers (MDIs) and dry powder inhalers (DPIs). Factors affecting inhalation technique include ongoing training, inhalation device, spacer use (with MDIs), and natural ability. Model parameters were derived from a literature review or were estimated from clinical experience. Analyses demonstrated that most patients receive a fraction of prescribed ICS doses over time. The model may be used to better understand the impact of increasing ICS dosages and to estimate the likelihood of patients being underdosed.

Inhaled corticosteroids for asthma therapy: patient compliance, devices, and inhalation technique.

BACKGROUND: Patient compliance, inhalation devices, and inhalation techniques influence the effectiveness of inhaled medications. METHODS: This article presents the results of a systematic literature review of studies measuring compliance with inhaled corticosteroids, measuring inhalation technique with different inhalation devices, and estimating the proportion of inhaled drug that is deposited in the lung. RESULTS: Overall, patients took the recommended doses of inhaled medication on 20 to 73% of days. Frequency of efficient inhalation technique ranged from 46 to 59% of patients. Education programs have been shown to improve compliance and inhalation techniques. The lung deposition achieved with different inhalers depends on particle size as well as inhaler technique. CONCLUSION: This review demonstrates that multiple factors may come between a prescription of an inhaled corticosteroid and the arrival of that medicine at its target organ, the lung.

Therapeutic outcomes monitoring: application of pharmaceutical care guidelines to community pharmacy.

OBJECTIVE: To design a pharmaceutical care model, and develop and field test a set of community pharmacy guidelines and practice support materials--Therapeutic Outcomes Monitoring (TOM) modules. DESIGN: Concept interviews with pharmacists, physicians, and patients; development and field testing of practice guidelines. SETTING: Community pharmacies. PARTICIPANTS: Five independent, five chain, and two clinic site pharmacies. INTERVENTIONS: A prototype TOM module for asthma was developed through a seven-step process. Concept interviews were held with pharmacists, physicians, and patients to determine the desirability and feasibility of the TOM concept, prototype, and materials. Two field tests were completed and modifications made. Results were gathered through further concept interviews at the completion of the second field tests. MAIN OUTCOME MEASURES: Participants' opinions and experiences. RESULTS: Pharmacists, physicians, and patients expressed favorable attitudes about community pharmacists' participation in this pharmaceutical care model. Of the 12 participating pharmacists, 7 successfully implemented TOM in their practice sites and participated in the project throughout the testing; 49 patients were recruited into the study; and 22 patients remained in the program at the end of the second field test. In providing TOM services to these patients, the two most problematic areas for the pharmacists were in documenting care and reporting to physicians. A final phase of the TOM project has not been conducted in the United States because of insufficient numbers of patients for evaluating patient outcomes. CONCLUSION: The TOM project was successful from a technical but not a marketing perspective. Useful practice guidelines can be written and taught to pharmacists. Enrollment of patients was difficult, and the concept is not likely to spread spontaneously within the existing market for pharmaceutical services.

Cost of acid peptic disorders in a managed-care organization.

The purpose of this study was to determine the cost of managing ambulatory patients with symptoms of acid peptic disorders in a managed-care organization under actual clinical conditions. Study data were collected in a large independent practice association model health maintenance organization in Gainesville, Florida, from prescription records maintained in a computerized database and from patient medical records. Patients had to be started on a histamine2-receptor antagonist (H2RA) or the proton pump inhibitor omeprazole between 1992 and 1994. A total of 113 patients qualified for inclusion in the study; 57 received H2RAs, 27 received omeprazole, and 29 received combination therapy. The costs of procedures, physician visits, and drug therapy were considered in the economic evaluation. Costs were evaluated using two methods: the capitation total cost (CTC) and the fee-for-service total cost (FSTC). The mean CTC and FSTC for managing a patient with acid peptic symptoms for 6 months were $382 +/- 356 (range, $14 to $1820) and $456 +/- 368 (range, $52 to $1925), respectively. Drug costs represented 52% of the total FSTC and 62% of the total CTC. Drug costs were followed by the costs for encounters with primary care physicians, endoscopy, referral to specialists, and upper gastrointestinal (UGI) tract procedures. Documented outcomes were available for 85 patients. Compared with patients receiving H2RAs (n = 41), patients receiving omeprazole (n = 18) had significantly lower FSTCs ($317 +/- 219 compared with $423 +/- 307, respectively); diagnostic testing costs (for endoscopy, $0 compared with $44 +/- 119, respectively; for UGI procedures, $22 +/- 42 compared with $55 +/- 54, respectively); physician encounter costs ($66 +/- 40 compared with $86 +/- 38, respectively); and referral to specialist costs ($0 compared with $18 +/- 60, respectively). Patients receiving omeprazole also had more positive clinical outcomes than patients receiving H2RAs (78% compared with 49%, respectively), resulting in a more favorable cost of producing a successful outcome compared with patients receiving an H2RA. The cost of success was $407 for patients treated with omeprazole compared with $869 for patients treated with H2RAs. The findings of this analysis conducted under actual clinical conditions support findings of randomized clinical trials showing the cost-effectiveness of proton pump inhibitors.

Evaluating the value, accuracy, and operational feasibility of DUE criteria.

The purpose of this investigation was to evaluate the value, accuracy, and operational feasibility of indicators/criteria in a drug use evaluation (DUE) examining IV histamine2-receptor antagonists (H2-RA). Pharmacists in 40 hospitals collected DUE data concurrent with hospital stays on a total of 1,200 patients. After completing the DUE, pharmacist data collectors were asked to evaluate each DUE criterion. Most reported that criteria relating to indications for use, therapeutic drug monitoring, and adverse drug reactions/drug interactions should be included in a DUE, but some criteria were not easy to collect or were inaccurate. The data suggest the need to carefully select DUE criteria that can be used for continuous improvements that meet JCAHO accreditation requirements.

A pharmacoeconomic analysis of IV H2-receptor antagonist use in 40 hospitals.

The objectives of this study were to determine (1) the expenditures of hospitals for IV histamine2-receptor antagonists (H2-RA), and (2) the cost savings that might be realized if only a single IV H2-RA was purchased for use. Forty hospitals provided data about purchase prices for each IV H2-RA dosage form purchased (cimetidine, ranitidine, and famotidine), the number of each dosage form used during the 12-month study period, purchase price and extent of usage for supplies, labor costs for preparing and administering IV H2-RAs, and IV H2-RA dosage schedules. The study showed that most hospitals were spending more money for IV H2-RAs than necessary given the pricing structures of the three products available to them at the time of this study. Also, that significant cost savings could be realized if a single H2-RA was used exclusively.

Risk for adverse events among patients receiving intravenous histamine2-receptor antagonists.

OBJECTIVE: To identify risk factors for adverse drug reactions (ADRs) in patients receiving intravenous histamine2-receptor antagonists (H2-RAs). DESIGN: The study hypothesis was evaluated by performing a logistic regression procedure with a backward elimination of the explanatory variables associated with ADRs. MAIN OUTCOME MEASURES: ADRs temporally associated with the use of intravenous H2-RAs served as the dependent variable. Background information about the patients and drug use evaluation criteria in three general areas were entered into the regression analysis. SETTING: Hospitals were selected from the southeastern US, based on their willingness to participate and their characteristics. Participating hospitals exhibited a variety of sizes and ownership arrangements. PATIENTS: 1200 adult patients who were receiving intravenous H2-RAs. RESULTS: Seven percent of patients experienced a presumed ADR (PADR) to intravenous H2-RAs. The only risk factor for ranitidine was for patients who did not have their dosage corrected for renal function ("overdose"); these patients were twice as likely to experience a PADR compared with patients who received the correct dosage as determined by their renal function. Two risk factors for cimetidine were identified: (1) patients taking cimetidine with another medication known to cause a drug interaction; and (2) patient age. No risk factors were identified for famotidine. CONCLUSIONS: The two risk factors for ADRs identified in this study are preventable. Healthcare providers should strive to prevent ADRs by adjusting patients' dosages based on their renal function and by monitoring patients receiving cimetidine with another medication known to interact with cimetidine.