Cyclopentadienones via a tandem C-cyclopropylnitrone cyclization-cycloreversion sequence.

Aldonitrones derived from spiro[2.4]hepta-4,6-diene-1-carbaldehyde and its benzo analog undergo a tandem uncatalyzed intramolecular cyclopropane-nitrone cyclization-5,6-dihydro-1,2-oxazine cycloreversion to give cyclopentadienones. Similarly, the NH-nitrone generated in situ from spiro[cyclopropane-1,1'-indene]carbaldehyde oxime leads to benzocyclopentadienone (1H-inden-1-one) by the same mechanism. DFT calculations are in favor of a concerted yet highly asynchronous pathway for the cyclizations. Control experiments with the dihydro and tetrahydro derivatives show that the spirocyclopentadiene unit is essential for the success of the reaction, invoking spiroconjugative effects for increased cyclopropane reactivity.

Oxidative dehydrogenation of ethane on dynamically rearranging supported chloride catalysts.

Ethane is oxidatively dehydrogenated with a selectivity up to 95% on catalysts comprising a mixed molten alkali chloride supported on a mildly redox-active Dy2O3-doped MgO. The reactive oxyanionic OCl(-) species acting as active sites are catalytically formed by oxidation of Cl(-) at the MgO surface. Under reaction conditions this site is regenerated by O2, dissolving first in the alkali chloride melt, and in the second step dissociating and replenishing the oxygen vacancies on MgO. The oxyanion reactively dehydrogenates ethane at the melt-gas phase interface with nearly ideal selectivity. Thus, the reaction is concluded to proceed via two coupled steps following a Mars-van-Krevelen-mechanism at the solid-liquid and gas-liquid interface. The dissociation of O2 and/or the oxidation of Cl(-) at the melt-solid interface is concluded to have the lowest forward rate constants. The compositions of the oxide core and the molten chloride shell control the catalytic activity via the redox potential of the metal oxide and of the OCl(-). Traces of water may be present in the molten chloride under reaction conditions, but the specific impact of this water is not obvious at present. The spatial separation of oxygen and ethane activation sites and the dynamic rearrangement of the surface anions and cations, preventing the exposure of coordinatively unsaturated cations, are concluded to be the origin of the surprisingly high olefin selectivity.

Effect of allylic groups on S(N)2 reactivity.

The activating effects of the benzyl and allyl groups on S(N)2 reactivity are well-known. 6-Chloromethyl-6-methylfulvene, also a primary, allylic halide, reacts 30 times faster with KI/acetone than does benzyl chloride at room temperature. The latter result, as well as new experimental observations, suggests that the fulvenyl group is a particularly activating allylic group in S(N)2 reactions. Computational work on identity S(N)2 reactions, e.g., chloride(-) displacing chloride(-) and ammonia displacing ammonia, shows that negatively charged S(N)2 transition states (tss) are activated by allylic groups according to the Galabov-Allen-Wu electrostatic model but with the fulvenyl group especially effective at helping to delocalize negative charge due to some cyclopentadienide character in the transition state (ts). In contrast, the triafulvenyl group is deactivating. However, the positively charged S(N)2 transition states of the ammonia reactions are dramatically stabilized by the triafulvenyl group, which directly conjugates with a reaction center having S(N)1 character in the ts. Experiments and calculations on the acidities of a variety of allylic alcohols and carboxylic acids support the special nature of the fulvenyl group in stabilizing nearby negative charge and highlight the ability of fulvene species to dramatically alter the energetics of processes even in the absence of direct conjugation.

Real-World Evidence to Support EU Regulatory Decision Making-Results From a Pilot of Regulatory Use Cases.

Studies using real-world data (RWD) can complement evidence from clinical trials and fill evidence gaps during different stages of a medicine's lifecycle. This review presents the experience resulting from the European Medicines Agency (EMA) pilot to generate RWE to support evaluations by EU regulators and down-stream decision makers from September 2021 to February 2023. A total of 61 research topics were identified for RWE generation during this period, covering a wide range of research questions, primarily generating evidence on medicines safety (22, 36%), followed by questions on the design and feasibility of clinical trials (11, 18%), drug utilization (10, 16%), clinical management (10, 16%), and disease epidemiology. A significant number of questions were related to the pediatric population and/or rare diseases. A total of 27 regulatory-led RWD studies have been conducted. Most studies were descriptive and aimed at estimating incidence and prevalence rates of clinical outcomes including adverse events or to evaluate medicines utilization. The review highlights key learnings to guide further efforts to enable the use and establish the value of real-world evidence (RWE) for regulatory decisions. For instance, there is a need to access additional fit-for-purpose and representative data, and to explore further means to provide timely evidence that meets regulatory timelines. The need for early interactions and close collaboration with study requesters, e.g., from the Agency's scientific Committees, to better understand the research question is equally important. Finally, the review provides our perspective on the way forward to maximize the potential of regulatory-led RWE generation.

Temperature-dependent, competitive 1,3-acyl shift versus decarbonylation of a cyclopropanone intermediate.

Photooxygenation of 1,1,3-trimethyl-1,2-dihydropentalene gives an unstable endoperoxide which upon decomposition delivers a bicyclic cyclopropanone intermediate; this species either extrudes CO to give a cycloheptadienone or undergoes a 1,3-acyl shift, both processes occurring most likely in a stepwise manner via diradical intermediates. Alternatively, C3a-C4 cleavage in the dioxygen diradical derived from the endoperoxide yields a 2-cyclopropyl substituted cyclopentadienone epoxide.

A Passive Back-Support Exoskeleton for Manual Materials Handling: Reduction of Low Back Loading and Metabolic Effort during Repetitive Lifting.

OCCUPATIONAL APPLICATIONSGlobalization and eCommerce continue to fuel unprecedented growth in the logistics and warehousing markets. Simultaneously, the biggest bottleneck for these industries is their human capital. Where automation and robotic solutions fail to deliver a return on investment, humans frequently take over handling tasks that place harmful loads and strains on the body. Occupational exoskeletons can reduce fatigue and strain by supporting the lower spine and are designed to prevent work-related musculoskeletal disorders and other injuries. They are a mid- to long-term investment for industries to improve ergonomic conditions in workplaces, with the potential for reducing absences from work, sick days logged, and workers compensation claims. To examine the effectiveness of the newly introduced Paexo Back exoskeleton, a study was completed with 10 participants who completed manual load handling tasks with and without the exoskeleton. Key findings include significant reductions in metabolic effort and low back loading when the exoskeleton is worn.

TECHNICAL ABSTRACTBackground: Work-related low back pain is a major threat to workers and society. Some new commercial and prototype exoskeletons are designed to specifically control the development of such disorders. Some beneficial effects of these exoskeletons have been reported earlier. Purpose: Determine the potential benefits of a newly introduced exoskeleton, Paexo Back, which is designed to reduce low back loading during lifting tasks. Methods: Ten healthy subjects participated in this study. To replicate a typical workplace situation, a repetitive lifting task with and without the exoskeleton was performed. For 5-min periods, the participants repeatedly lifted a 10-kg box from the floor onto a table and then placed it back on the floor. Effects of exoskeleton use were assessed using a diverse set of outcomes. Oxygen uptake and heart rate were measured using a wireless spiroergometry system. Activation levels of back, abdominal, and thigh muscles were also measured using a wireless electromyographic system. Kinematic data were recorded using an optoelectronic device, and ground reaction forces were measured with two force plates. Joint compression forces in the lower spine (L4/L5 and L5/S1) were estimated using the AnyBody™ Modeling System during the upward lifting portion of the lifting task (bringing the box to the table). Results: Using the exoskeleton resulted in significant reductions in oxygen rate (9%), activation of the back and thigh muscles (up to 18%), and peak and mean compression forces at L4/L5 (21%) and L5/S1 (20%). Conclusions: These results show that using the tested exoskeleton for a lifting task contributes to an increased metabolic efficiency, a reduction in the back muscle activation required to conduct the task, and a reduction in low back loading.

Assessing the efficiency of exoskeletons in physical strain reduction by biomechanical simulation with AnyBody Modeling System.

Introduction: Recently, many industrial exoskeletons for supporting workers in heavy physical tasks have been developed. However, the efficiency of exoskeletons with regard to physical strain reduction has not been fully proved, yet. Several laboratory and field studies have been conducted, but still more data, that cannot be obtained solely by behavioral experiments, are needed to investigate effects on the human body. Methods: This paper presents an approach to extend laboratory and field research with biomechanical simulations using the AnyBody Modeling System. Based on a dataset recorded in a laboratory experiment with 12 participants using the exoskeleton Paexo Shoulder in an overhead task, the same situation was reproduced in a virtual environment and analyzed with biomechanical simulation. Results: Simulation results indicate that the exoskeleton substantially reduces muscle activity and joint reaction forces in relevant body areas. Deltoid muscle activity and glenohumeral joint forces in the shoulder were decreased between 54 and 87%. Simultanously, no increases of muscle activity and forces in other body areas were observed. Discussion: This study demonstrates how a simulation framework could be used to evaluate changes in internal body loads as a result of wearing exoskeletons. Biomechanical simulation results widely agree with experimental measurements in the previous laboratory experiment and supplement such by providing an insight into effects on the human musculoskeletal system. They confirm that Paexo Shoulder is an effective device to reduce physical strain in overhead tasks. The framework can be extended with further parameters, allowing investigations for product design and evaluation.

The hydroarylation reaction--scope and limitations.

The synthetic potential of stereoselective, palladium-catalyzed hydro(het)arylation reactions of bi-, tri- and tetracyclic (hetero)alkenes in the presence of phospines and arsines as highly efficient ligands was studied. The mechanism of this reductive Heck reaction becomes more complex in the case of benzonorbornenes. Hydroarylation of diazabicyclo-[2.2.1]heptenes provides a stereoselective access to aryldiaminocyclopentanes. Electron-deficient arylpalladium complexes shift the reaction towards the product of a formal 1,2-hydrazidoarylation reaction of 1,3-cyclopentadiene by a stereoselective C-N cleavage. Due to steric reasons, rigid bicyclo[2.2.2]octenes react slower in hydroarylation reactions than the corresponding bicyclo[2.2.1]heptenes. The more flexible bicyclo[4.2.2]decene system already tends to undergo domino-Heck reactions, even under reductive conditions. When a tetracyclic cis-allylcyclopropane is carbopalladated in the presence of formates, the neighboring cyclopropane ring is attacked in the first reported example of a pi,sigma domino-Heck reaction.

Current Statistical Considerations and Regulatory Perspectives on the Planning of Confirmatory Basket, Umbrella, and Platform Trials.

Master protocols have received a growing interest during the last years. By assigning patients to specific substudies, they aim at targeting and accelerating clinical development. Given their complexity, basket, umbrella, and platform designs have raised challenging regulatory and statistical questions, especially the control of multiplicity in confirmatory trials. In basket trials, regulatory assessment of the benefit/risk in pooled populations and choice of the treatment indication is challenging. We provide here our perspectives on these topics. In master protocols, as long as the statistical hypotheses tested between the different substudies are independent, no supplementary adjustment for multiplicity over the different substudies should be required. Moreover, sharing a control arm within an umbrella or a platform trial investigating different drugs would not require a correction for the type I error rate, whereas the chance of multiple false positive regulatory decisions should be recognized. In basket trials, pooling across substudies requires a rationale supporting the intended indication and should be preplanned. Assessment of the benefit/risk in pooled target populations can be complicated by differences in design or in efficacy/safety signals between the substudies. While trials governed by a master protocol can offer logistic and financial advantages, more experience is needed to gain a deeper insight into this novel framework.

An exceptionally simple and efficient synthesis of 6-methyl-6-vinylfulvene, and its oxidative transformations.

A new efficient synthesis of 6-methyl-6-vinylfulvene was developed, starting from the 6-(2-hydroxyethyl)-6-methylfulvene. With larger quantities of the title compound in hand, its photooxygenation with singlet oxygen was studied. Cyclization of the cyclopropanone intermediate to both vinyl moieties in the unsaturated system was observed, whereas the saturated endoperoxide gave mostly the cyclopentenone derivative. m-CPBA attacks exclusively the endocyclic double bonds and gives the 3-cyclopentenones via the unstable epoxides.

Photooxygenation of 5-dialkylamino-4-pyrrolin-3-ones. Synthesis of highly functionalized ureas, 2-oxazolidinones, and 2-oxazolinones.

5-Dialkylamino-4-pyrrolin-3-ones, available from cyclocondensation of amidines with dimethyl acetylenedicarboxylate (DMAD), undergo rapid singlet oxygenation to give highly functionalized ureas by way of a 1,2-dioxetane cleavage of the initially formed [2 + 2] cycloadducts. These latter compounds undergo cyclization to 2-oxazolidinones in MeOH. Catalytic hydrogenation of the ureas in EtOAc gives 2-oxazolinones. The DBU-DMAD adduct undergoes photooxygenation by an entirely different pathway to give a large ring heterocycle.

Unusual endoperoxide isomerizations: a convenient entry into 2-vinyl-2-cyclopentenones from saturated fulvene endoperoxides.

An unusual peroxide base promoted isomerization was uncovered. Saturated endoperoxides derived from fulvenes give rise to 2-vinyl-2-cyclopentenones upon treatment with DBU in CH(2)Cl(2) in a one-pot reaction. This methodology was applied to a convenient synthesis of dihydrojasmone. Moreover, functional groups placed on the side chain at C-6 participate in the base catalyzed isomerizations via conjugate attack at the enone moiety to give 2-cyclopentenones carrying oxygen heterocycles at C2.

Negative expiratory pressure: a new tool for evaluating lung function in children?

The negative expiratory pressure technique (NEP) has been applied in adults with chronic obstructive pulmonary disease (COPD), demonstrating flow limitation in many of these patients. Because this technique does not require patient cooperation, it is of potential interest for application in the pediatric population. This study was performed to test the feasibility of NEP in children, and to further investigate it in children with asthma and cystic fibrosis (CF). We performed NEP (0.3-0.7 kPa) measurements in 14 healthy children (13.3 years, +/- 2.4), in 12 children with asthma (11.7 years, +/- 3.0), and in 17 children with CF (13.3 years, +/- 2.7). NEP-derived flow-volume loops were visually analyzed for flow limitation at tidal breathing. In addition, expiratory flow at 50% of tidal volume (TEF(50)) was measured. In healthy children, the intraclass coefficient of correlation was 77%, and intraindividual short- and long-term variability was 5.8% and 10.8%, respectively. In asthmatics, TEF(50) was lower compared with controls, and increased after inhalation of salbutamol. However, appropriate size-correction has still to be established. Measurement of TEF(50) using NEP is feasible in children. Despite good reproducibility in individual patients, the high intersubject variability may limit its usefulness as a clinical tool. In addition, the lack of flow limitation using NEP even in severely obstructed patients with CF warrants further investigation.

Improvements of lung function in cystic fibrosis.

Improved care for patients with cystic fibrosis (CF) has led to their improved survival. We analyzed retrospectively whether improvements in lung function (LF) could be detected in our CF patients over the decade 1980-1990. In 72 patients, 153 LF measurements were performed in their first year of life (1980-1991), and then 189 LF measurements were performed again in 60 of those patients during their sixth year of life (1987-1997). Regression analysis was performed on LF parameters at age 6 years. When adjusting for weight, height, gender, and LF in the first year of life, the date of subsequent measurement was positively associated with FEV(1) (P < 0.01) and MEF(50%) (P < 0.05) and negatively with FRC(pleth) (P < 0.05). The proposed model predicts a child's FEV(1) at age 6 to be 75% of predicted if born in 1980, but 108% of predicted when born in 1990. Improved CF care is the most likely explanation for this observation.

The virtual articulator in dentistry: concept and development.

Virtual Reality (VR) technology is one of the most important innovations for research, development, and industrial production. In dentistry, VR technology will be useful in providing better education through simulation and in enhancing working procedures that are conventionally limited, e.g., the mechanical articulator. It is the purpose of this article to present concepts and strategies for a future replacement of the mechanical articulator by a virtual one.

["Nursing care visit: possibilities and limits". An empirical study in Bremen, Hamburg, Mecklenburg-Vorpommern, Lower Saxony and Schleswig-Holstein]. / "Pflegevisite: Möglichkeiten und Grenzen". Eine empirische Untersuchung in den Bundesländern Bremen, Hamburg, Mecklenburg-Vorpommern, Niedersachsen und Schleswig-Holstein.

This study examines the distribution, understanding and objectives of nursing visits as well as the implementation and the experience with nursing visits in 87 hospitals in North Germany (Bremen, Lower Saxony, Hamburg, Schleswig-Holstein and Mecklenburg-Western Pomerania). The survey was conducted using a questionnaire. It was found that nursing visits are implemented in 31% of the departments. By means of the nursing visit the patients are involved in the nursing process. The objectives of nursing visits are patient orientation. and the improvement of the nursing quality. The nursing visit is criticised because of both the level of organisation and the time spent on nursing visits as well as the lack of training, maintaining confidentiality and questions of data protection. The study contributes to a better understanding of nursing visits and a clearer definition of the term. It is the first empirical study of this type that has been conducted in Germany.

Microbiological contamination in counterfeit and unapproved drugs.

BACKGROUND: Counterfeit and unapproved medicines are inherently dangerous and can cause patient injury due to ineffectiveness, chemical or biological contamination, or wrong dosage. Growth of the counterfeit medical market in developed countries is mainly attributable to life-style drugs, which are used in the treatment of non-life-threatening and non-painful conditions, such as slimming pills, cosmetic-related pharmaceuticals, and drugs for sexual enhancement. One of the main tasks of health authorities is to identify the exact active pharmaceutical ingredients (APIs) in confiscated drugs, because wrong API compounds, wrong concentrations, and/or the presence of chemical contaminants are the main risks associated with counterfeit medicines. Serious danger may also arise from microbiological contamination. We therefore performed a market surveillance study focused on the microbial burden in counterfeit and unapproved medicines. METHODS: Counterfeit and unapproved medicines confiscated in Canada and Austria and controls from the legal market were examined for microbial contaminations according to the US and European pharmacopoeia guidelines. The microbiological load of illegal and legitimate samples was statistically compared with the Wilcoxon rank-sum test. RESULTS: Microbial cultivable contaminations in counterfeit and unapproved phosphodiesterase type 5 inhibitors were significantly higher than in products from the legal medicines market (p < 0.0001). Contamination levels exceeding the USP and EP limits were seen in 23% of the tested illegal samples in Canada. Additionally, microbiological contaminations above the pharmacopoeial limits were detected in an anabolic steroid and an herbal medicinal product in Austria (6% of illegal products tested). CONCLUSIONS: Our results show that counterfeit and unapproved pharmaceuticals are not manufactured under the same hygienic conditions as legitimate products. The microbiological contamination of illegal medicinal products often exceeds USP and EP limits, representing a potential threat to consumer health.

1,2-Dihydropentalenes from fulvenes by [6 + 2] cycloadditions with 1-isopropenylpyrrolidine.

In situ generated acetone pyrrolidine enamine undergoes [6 + 2] cycloadditions with fulvenes to give 1,2-dihydropentalenes. This ring annulation method works particularly well with 6-monosubstituted fulvenes and is subject to steric hindrance at C-6 of the fulvene. On the basis of mechanistic studies, optimal conditions have been developed for a one-pot synthesis of 1,2-dihydropentalenes using catalytic amounts of pyrrolidine.

Association between a single-pass whole-body computed tomography policy and survival after blunt major trauma: a retrospective cohort study.

INTRODUCTION: Single-pass, whole-body computed tomography (pan-scan) remains a controversial intervention in the early assessment of patients with major trauma. We hypothesized that a liberal pan-scan policy is mainly an indicator of enhanced process quality of emergency care that may lead to improved survival regardless of the actual use of the method. METHODS: This retrospective cohort study included consecutive patients with blunt trauma referred to a trauma center prior to (2000 to 2002) and after (2002 to 2007) the introduction of a liberal single-pass pan-scan policy. The overall mortality between the two periods was compared and stratified according to the availability and actual use of the pan-scan. Logistic regression analysis was employed to adjust mortality estimates for demographic and injury-related independent variables. RESULTS: The study comprised 313 patients during the pre-pan-scan period, 223 patients after the introduction of the pan-scan policy but not undergoing a pan-scan and 608 patients undergoing a pan-scan. The overall mortality was 23.3, 14.8 and 7.9% (P < 0.001), respectively. By univariable logistic regression analysis, both the availability (odds ratio (OR) 0.57, 95% confidence interval (CI): 0.36 to 0.90) and the actual use of the pan-scan (OR 0.28, 95% CI: 0.19 to 0.42) were associated with a lower mortality. The final model contained the Injury Severity Score, the Glasgow Coma Scale, age, emergency department time and the use of the pan-scan. 2.7% of the explained variance in mortality was attributable to the use of the pan-scan. This contribution increased to 7.1% in the highest injury severity quartile. CONCLUSIONS: In this study, a liberal pan-scan policy was associated with lower trauma mortality. The causal role of the pan-scan itself must be interpreted in the context of improved structural and process quality, is apparently moderate and needs further investigation with regard to the diagnostic yield and changes in management decisions. (The Pan-Scan for Trauma Resuscitation [PATRES] Study Group, ISRCTN35424832 and ISRCTN41462125).

Triphenylphosphine reduction of saturated endoperoxides.

Triphenylphosphine reduction of saturated endoperoxides derived from 6,6-dimethylfulvene and spiro[2.4]hepta-4,6-diene in the presence of nucleophiles results in the formation of products that mainly stem from deoxygenation followed by carbocation formation. Nucleophilic attack by solvent proceeds by an S(N)1 like mechanism; allyl shifts and cyclopropylcarbinyl-cyclobutyl rearrangements also occur. With the systems lacking carbocation-stabilizing groups, the deoxygenation step is preceded by attack of H(2)O at the phosphorus.