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This short review focuses on enantiopure planar chiral [2.2]paracyclophanes (pCps), a fascinating class of molecules that possess an unusual three-dimensional core and intriguing physicochemical properties. In the first part of the review, different synthetic strategies for preparing optically active pCps are described. Although classical resolution methods based on the synthesis and separation of diastereoisomeric products still dominate the field, recent advances involving the kinetic resolution of racemic compounds and the desymmetrization of meso derivatives open up new possibilities to access enantiopure key intermediates on synthetically useful scales. Due to their advantageous properties including high configurational and chemical stability, [2.2]paracyclophanes are increasingly employed in various research fields, ranging from stereoselective synthesis to material sciences. The applications of [2.2]paracyclophanes in asymmetric organocatalysis are described in the second part of the review. While historically enantiopure pCps have been mainly employed by organic chemists as chiral ligands in transition-metal catalysis, these compounds can also be used as efficient catalysts in metal-free reactions and may inspire the development of new transformations in the near future., (© 2021 Wiley Periodicals LLC.)

Background: This an update of the review first published in 2009.Major abdominal and pelvic surgery carries a high risk of venous thromboembolism (VTE). The efficacy of thromboprophylaxis with low molecular weight heparin (LMWH) administered during the in-hospital period is well-documented, but the optimal duration of prophylaxis after surgery remains controversial. Some studies suggest that patients undergoing major abdominopelvic surgery benefit from prolongation of the prophylaxis up to 28 days after surgery., Objectives: To evaluate the efficacy and safety of prolonged thromboprophylaxis with LMWH for at least 14 days after abdominal or pelvic surgery compared with thromboprophylaxis administered during the in-hospital period only in preventing late onset VTE., Search Methods: We performed electronic searches on 28 October 2017 in the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, LILACS and registered trials (Clinicaltrials.gov October 28, 2017 and World Health Organization International Clinical Trials Registry Platform (ICTRP) 28 October 2017). Abstract books from major congresses addressing thromboembolism were handsearched from 1976 to 28 October 2017, as were reference lists from relevant studies., Selection Criteria: We assessed randomized controlled clinical trials (RCTs) comparing prolonged thromboprophylaxis (≥ fourteen days) with any LMWH agent with placebo, or other methods, or both to thromboprophylaxis during the admission period only. The population consisted of persons undergoing abdominal or pelvic surgery for both benign and malignant pathology. The outcome measures included VTE (deep venous thrombosis (DVT) or pulmonary embolism (PE)) as assessed by objective means (venography, ultrasonography, pulmonary ventilation/perfusion scintigraphy, spiral computed tomography (CT) scan or autopsy). We excluded studies exclusively reporting on clinical diagnosis of VTE without objective confirmation., Data Collection and Analysis: Review authors identified studies and extracted data. Outcomes were VTE (DVT or PE) assessed by objective means. Safety outcomes were defined as bleeding complications and mortality within three months after surgery. Sensitivity analyses were also performed with unpublished studies excluded, and with study participants limited to those undergoing solely open and not laparoscopic surgery. We used a fixed-effect model for analysis., Main Results: We identified seven RCTs (1728 participants) evaluating prolonged thromboprophylaxis with LMWH compared with control or placebo. The searches resulted in 1632 studies, of which we excluded 1528. One hundred and four abstracts, eligible for inclusion, were assessed of which seven studies met the inclusion criteria.For the primary outcome, the incidence of overall VTE after major abdominal or pelvic surgery was 13.2% in the control group compared to 5.3% in the patients receiving out-of-hospital LMWH (Mantel Haentzel (M-H) odds ratio (OR) 0.38, 95% confidence interval (CI) 0.26 to 0.54; I 2 = 28%; moderate-quality evidence).For the secondary outcome of all DVT, seven studies, n = 1728, showed prolonged thromboprophylaxis with LMWH to be associated with a statistically significant reduction in the incidence of all DVT (M-H OR 0.39, 95% CI 0.27 to 0.55; I 2 = 28%; moderate-quality evidence).We found a similar reduction when analysis was limited to incidence in proximal DVT (M-H OR 0.22, 95% CI 0.10 to 0.47; I 2 = 0%; moderate-quality evidence).The incidence of symptomatic VTE was also reduced from 1.0% in the control group to 0.1% in patients receiving prolonged thromboprophylaxis, which approached significance (M-H OR 0.30, 95% CI 0.08 to 1.11; I 2 = 0%; moderate-quality evidence).No difference in the incidence of bleeding between the control and LMWH group was found, 2.8% and 3.4%, respectively (M-H OR 1.10, 95% CI 0.67 to 1.81; I 2 = 0%; moderate-quality evidence).No difference in mortality between the control and LMWH group was found, 3.8% and 3.9%, respectively (M-H OR 1.15, 95% CI 0.72 to 1.84; moderate-quality evidence).Estimates of heterogeneity ranged between 0% and 28% depending on the analysis, suggesting low or unimportant heterogeneity., Authors' Conclusions: Prolonged thromboprophylaxis with LMWH significantly reduces the risk of VTE compared to thromboprophylaxis during hospital admittance only, without increasing bleeding complications or mortality after major abdominal or pelvic surgery. This finding also holds true for DVT alone, and for both proximal and symptomatic DVT. The quality of the evidence is moderate and provides moderate support for routine use of prolonged thromboprophylaxis. Given the low heterogeneity between studies and the consistent and moderate evidence of a decrease in risk for VTE, our findings suggest that additional studies may help refine the degree of risk reduction but would be unlikely to significantly influence these findings. This updated review provides additional evidence and supports the previous results reported in the 2009 review.

Background: This an update of the review first published in 2009.Major abdominal and pelvic surgery carries a high risk of venous thromboembolism (VTE). The efficacy of thromboprophylaxis with low molecular weight heparin (LMWH) administered during the in-hospital period is well-documented, but the optimal duration of prophylaxis after surgery remains controversial. Some studies suggest that patients undergoing major abdominopelvic surgery benefit from prolongation of the prophylaxis up to 28 days after surgery., Objectives: To evaluate the efficacy and safety of prolonged thromboprophylaxis with LMWH for at least 14 days after abdominal or pelvic surgery compared with thromboprophylaxis administered during the in-hospital period only in preventing late onset VTE., Search Methods: We performed electronic searches on 28 October 2017 in the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, LILACS and registered trials (Clinicaltrials.gov October 28, 2017 and World Health Organization International Clinical Trials Registry Platform (ICTRP) 28 October 2017). Abstract books from major congresses addressing thromboembolism were handsearched from 1976 to 28 October 2017, as were reference lists from relevant studies., Selection Criteria: We assessed randomized controlled clinical trials (RCTs) comparing prolonged thromboprophylaxis (≥ fourteen days) with any LMWH agent with placebo, or other methods, or both to thromboprophylaxis during the admission period only. The population consisted of persons undergoing abdominal or pelvic surgery for both benign and malignant pathology. The outcome measures included VTE (deep venous thrombosis (DVT) or pulmonary embolism (PE)) as assessed by objective means (venography, ultrasonography, pulmonary ventilation/perfusion scintigraphy, spiral computed tomography (CT) scan or autopsy). We excluded studies exclusively reporting on clinical diagnosis of VTE without objective confirmation., Data Collection and Analysis: Review authors identified studies and extracted data. Outcomes were VTE (DVT or PE) assessed by objective means. Safety outcomes were defined as bleeding complications within three months after surgery. Sensitivity analyses were also performed with unpublished studies excluded, and with study participants limited to those undergoing solely open and not laparoscopic surgery. We used a fixed-effect model for analysis., Main Results: We identified seven RCTs (1728 participants) evaluating prolonged thromboprophylaxis with LMWH compared with control or placebo. The searches resulted in 1632 studies, of which we excluded 1528. One hundred and four abstracts, eligible for inclusion, were assessed of which seven studies met the inclusion criteria.For the primary outcome, the incidence of overall VTE after major abdominal or pelvic surgery was 13.2% in the control group compared to 5.3% in the patients receiving out-of-hospital LMWH (Mantel Haentzel (M-H) odds ratio (OR) 0.38, 95% confidence interval (CI) 0.26 to 0.54; I 2 = 28%; seven studies, n = 1728; moderate-quality evidence).For the secondary outcome of all DVT, seven studies, n = 1728, showed prolonged thromboprophylaxis with LMWH to be associated with a statistically significant reduction in the incidence of all DVT (M-H OR 0.39, 95% CI 0.27 to 0.55; I 2 = 28%; moderate-quality evidence).We found a similar reduction when analysis was limited to incidence in proximal DVT (M-H OR 0.22, 95% CI 0.10 to 0.47; I 2 = 0%; moderate-quality evidence).The incidence of symptomatic VTE was also reduced from 1.0% in the control group to 0.1% in patients receiving prolonged thromboprophylaxis (M-H OR 0.30, 95% CI 0.08 to 1.11; I 2 = 0%; moderate-quality evidence).No difference in the incidence of bleeding between the control and LMWH group was found, 2.8% and 3.4%, respectively (HM-H OR 1.10, 95% CI 0.67 to 1.81; I 2 = 0%; seven studies, n = 2239; moderate-quality evidence).Estimates of heterogeneity ranged between 0% and 28% depending on the analysis, suggesting low or unimportant heterogeneity., Authors' Conclusions: Prolonged thromboprophylaxis with LMWH significantly reduces the risk of VTE compared to thromboprophylaxis during hospital admittance only, without increasing bleeding complications after major abdominal or pelvic surgery. This finding also holds true for DVT alone, and for both proximal and symptomatic DVT. The quality of the evidence is moderate and provides moderate support for routine use of prolonged thromboprophylaxis. Given the low heterogeneity between studies and the consistent and moderate evidence of a decrease in risk for VTE, our findings suggest that additional studies may help refine the degree of risk reduction but would be unlikely to significantly influence these findings. This updated review provides additional evidence and supports the previous results reported in the 2009 review.

This paper revisits the debate on the 'red herring', viz. the claim that population ageing will not have a significant impact on health care expenditure (HCE). It decomposes HCE into seven components, includes both survivors and deceased individuals, and estimates a two-part model of the demand for health care services, using a large Swiss data set for 1999. It finds no or weak age effects on HCE for the components of HCE when proximity to death is controlled for, and points to differences between users and non-users of long-term care (LTC). For deceased non-users of LTC services, a falling age curve for all components of HCE except for inpatient care is observed, while survivors show a weak age effect in ambulatory and inpatient care once proximity to death is controlled for. As to surviving users of LTC services, their probability of incurring LTC expenses markedly increases in old age, while most of the components of their conditional HCE show a decreasing age profile. Thus, a 'school of red herrings' can be claimed to exist-with the possible exception of LTC, where ageing might matter regardless of proximity to death., (John Wiley & Sons, Ltd.)

Clinical epidemiology generally uses the receiver operating characteristic curve to summarize the accuracy of a diagnostic test and to compare the relative performance of different tests. This paper extends this concept to include the utility gains and losses of true and false test outcomes over the range of a priori risk. A utility index is developed first in situations where test accuracy is exogenously given, second where the test cutpoint can be chosen by the clinician according to the patient's a priori risk and preferences. By integrating over the a priori risk range, we derive an overall measure for a test's performance weighted by utility gains and losses. An example in prenatal diagnostics finally illustrates the clinical uses of the novel approach. Integrating patients' preference into clinical decision making will lead to different cutpoints and different assessments of test performance compared to unweighted policies.

Salas and Raftery allege that in our paper, (1) remaining life expectancy is an endogenous explanatory variable of health care expenditure and (2) the parameter designed to correct for sample selection bias in fact represents a hidden relationship between health care expenditure and age. We argue that claim (1) is not supported by the available empirical evidence, while claim (2) seems to derive from a too cursory reading of our paper., (Copyright 2001 John Wiley & Sons, Ltd.)

This paper studies the relationship between health care expenditure (HCE) and age, using longitudinal rather than cross-sectional data. The econometric analysis of HCE in the last eight quarters of life of individuals who died during the period 1983-1992 indicates that HCE depends on remaining lifetime but not on calendar age, at least beyond 65+. The positive relationship between age and HCE observed in cross-sectional data may be caused by the simple fact that at age 80, for example, there are many more individuals living in their last 2 years than at age 65. The limited impact of age on HCE suggests that population ageing may contribute much less to future growth of the health care sector than claimed by most observers., (Copyright 1999 John Wiley & Sons, Ltd.)

Combinatorial libraries employing the one-bead-one-compound technique are reviewed. Two distinguishing features characterize this technique. First, each compound is identified with a unique solid support, enabling facile segregation of active compounds. Second, the identity of a compound on a positively reacting bead is elucidated only after its biological relevance is established. Direct methods of structure identification (Edman degradation and mass spectroscopy) as well as indirect "coding" methods facilitating the synthesis and screening of nonpeptide libraries are discussed. Nonpeptide and "scaffold" libraries, together with a new approach for the discovery of a peptide binding motif using a "library of libraries," are also discussed. In addition, the ability to use combinatorial libraries to optimize initially discovered leads is illustrated with examples using peptide libraries.