Passive sampler housing and sorbent type determine aquatic micropollutant adsorption and subsequent bioassay responses.

The combination of integrative passive sampling and bioassays is a promising approach for monitoring the toxicity of polar organic contaminants in aquatic environments. However, the design of integrative passive samplers can affect the accumulation of compounds and therewith the bioassay responses. The present study aimed to determine the effects of sampler housing and sorbent type on the number of chemical features accumulated in polar passive samplers and the subsequent bioassay responses to extracts of these samplers. To this end, four integrative passive sampler configurations, resulting from the combination of polar organic chemical integrative sampler (POCIS) and Speedisk housings with hydrophilic-lipophilic balance and hydrophilic divinylbenzene sorbents, were simultaneously exposed at reference and contaminated surface water locations. The passive sampler extracts were subjected to chemical non-target screening and a battery of five bioassays. Extracts from POCIS contained a higher number of chemical features and caused higher bioassay responses in 91% of cases, while the two sorbents accumulated similar numbers of features and caused equally frequent but different bioassay responses. Hence, the passive sampler design critically affected the number of accumulated polar organic contaminants as well as their toxicity, highlighting the importance of passive sampler design for effect-based water quality assessment.

89Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer.

BACKGROUND: Programmed cell death protein 1 (PD-1) antibody treatment is standard of care for melanoma and non-small-cell lung cancer (NSCLC). Accurately predicting which patients will benefit is currently not possible. Tumor uptake and biodistribution of the PD-1 antibody might play a role. Therefore, we carried out a positron emission tomography (PET) imaging study with zirconium-89 (89Zr)-labeled pembrolizumab before PD-1 antibody treatment. PATIENTS AND METHODS: Patients with advanced or metastatic melanoma or NSCLC received 37 MBq (1 mCi) 89Zr-pembrolizumab (∼2.5 mg antibody) intravenously plus 2.5 or 7.5 mg unlabeled pembrolizumab. After that, up to three PET scans were carried out on days 2, 4, and 7. Next, PD-1 antibody treatment was initiated. 89Zr-pembrolizumab tumor uptake was calculated as maximum standardized uptake value (SUVmax) and expressed as geometric mean. Normal organ uptake was calculated as SUVmean and expressed as a mean. Tumor response was assessed according to (i)RECIST v1.1. RESULTS: Eighteen patients, 11 with melanoma and 7 with NSCLC, were included. The optimal dose was 5 mg pembrolizumab, and the optimal time point for PET scanning was day 7. The tumor SUVmax did not differ between melanoma and NSCLC (4.9 and 6.5, P = 0.49). Tumor 89Zr-pembrolizumab uptake correlated with tumor response (P trend = 0.014) and progression-free (P = 0.0025) and overall survival (P = 0.026). 89Zr-pembrolizumab uptake at 5 mg was highest in the spleen with a mean SUVmean of 5.8 (standard deviation ±1.8). There was also 89Zr-pembrolizumab uptake in Waldeyer's ring, in normal lymph nodes, and at sites of inflammation. CONCLUSION: 89Zr-pembrolizumab uptake in tumor lesions correlated with treatment response and patient survival. 89Zr-pembrolizumab also showed uptake in lymphoid tissues and at sites of inflammation.

Narcotic mechanisms of acute toxicity of chlorinated anilines in Folsomia candida (Collembola) revealed by gene expression analysis.

In order to clarify the mechanisms of reproductive toxicity in a QSAR approach, the transcriptional signatures upon the 2 day exposure to the 28 days EC50 of a series of increasingly chlorinated aniline compounds and 1,2,3,4-tetrachlorobenzene were measured in Folsomia candida. In general, the transcriptional patterns associated with all compounds revealed toxicity at the cellular membranes and hence components of narcosis type I, but a principal component analysis revealed a deviating response by the pentachloroaniline and 2,3,5,6-tetrachloroaniline exposure. Moreover the expression of a subset of mainly biotransformation related genes showed a significant relationship with the logK(ow,) which stresses the presence of narcosis type I. This was confirmed by GO term enrichment at the level of cellular component. Genes involved in the three phases of xenobiotic biotransformation exhibited strict compound specific transcription patterns, which may reflect biotransformation processes in F. candida. Additional toxic mechanisms were especially observed for the 2,3,5,6-tetrachloroaniline, which possible works as an uncoupler or inhibitor of electron transport systems, which is revealed by the up-regulation of genes that encode different members of the electron transport chain. The aniline and 2,3,4-trichloroaniline exposure caused the induction of genes in the ROS defense system. Additional toxicity mechanisms were less clear, but they include the attack of microbial pathogens for the six other compounds and for 2,3,5,6-tetrachloroaniline an effect on mitochondrial protein folding.

Condensed-phase effects on the structural properties of C6H5CN-BF3 and (CH3)3CCN-BF3: IR spectra, crystallography, and computations.

Condensed-phase effects on the structure and bonding of C(6)H(5)CN-BF(3) and (CH(3))(3)CCN-BF(3) are illustrated by a variety of results, and these are compared to analogous data for the closely related complex CH(3)CN-BF(3). For the most part, the structural properties of C(6)H(5)CN-BF(3) and (CH(3))(3)CCN-BF(3) are quite similar, not only in the gas phase but also in the solid state and in argon matrices. However, the structures do change significantly from medium to medium, and these changes are reflected in the data presented below. Specifically, the measured crystallographic structure of C(6)H(5)CN-BF(3) (s) has a B-N distance that is 0.17 A shorter than that in the equilibrium gas-phase structure obtained via B3LYP calculations. Notable differences between calculated gas-phase frequencies and measured solid-state frequencies for both C(6)H(5)CN-BF(3) and (CH(3))(3)CCN-BF(3) were also observed, and in the case of (CH(3))(3)CCN-BF(3), these data implicate a comparable difference between solid-state and gas-phase structure, even in the absence of crystallographic results. Frequencies measured in argon matrices were found to be quite similar for both complexes and also very near those measured previously for CH(3)CN-BF(3), suggesting that all three complexes adopt similar structures in solid argon. For C(6)H(5)CN-BF(3) and (CH(3))(3)CCN-BF(3), matrix IR frequencies differ only slightly from the computed gas-phase values, but do suggest a slight compression of the B-N bond. Ultimately, it appears that the varying degree to which these systems respond to condensed phases stems from subtle differences in the gas-phase species, which are highlighted through an examination of B-N distance potentials from B3LYP calculations. The larger organic substituents appear to stabilize the potential near 1.8 A, so that the structures are more localized in that region prior to any condensed-phase interactions. As a result, the condensed-phase effects on the structural properties of C(6)H(5)CN-BF(3) and (CH(3))(3)CCN-BF(3) are much less pronounced than those for CH(3)CN-BF(3).

Class IV charge models: a new semiempirical approach in quantum chemistry.

We propose a new criterion for defining partial charges on atoms in molecules, namely that physical observables calculated from those partial charges should be as accurate as possible. We also propose a method to obtain such charges based on a mapping from approximate electronic wave functions. The method is illustrated by parameterizing two new charge models called AM1-CM1A and PM3-CM1P, based on experimental dipole moments and, respectively, on AM1 and PM3 semiempirical electronic wave functions. These charge models yield rms errors of 0.30 and 0.26 D, respectively, in the dipole moments of a set of 195 neutral molecules consisting of 103 molecules containing H, C, N and O, covering variations of multiple common organic functional groups, 68 fluorides, chlorides, bromides and iodides, 15 compounds containing H, C, Si or S, and 9 compounds containing C-S-O or C-N-O linkages. In addition, partial charges computed with this method agree extremely well with high-level ab initio calculations for both neutral compounds and ions. The CM1 charge models provide a more accurate point charge representation of the dipole moment than provided by most previously available partial charges, and they are far less expensive to compute.

Health care as a right: some practical implications.

This article examines some of the important legal and moral issues raised by the recognition of a right to health care. The acceptance of such a right entails an ethical position critical of those societies which fail to provide for comprehensive access to basic health care facilities, and of those legal systems which do not impose a duty upon medical professionals to render aid in emergency situations. It will be found that, in the common-law world, judicial and legislative strategies to ensure a minimum level of medical care have proved inadequate due to the absence of such a duty. Correlative to a threshold right of access to health care is a moral obligation upon those providing medical services to respect the dignity and autonomy of their patients. A consistent moral or rights based approach has as a practical consequence the need to subordinate any purely scientific conception of the doctor's role to a set of legal and ethical standards which are appropriately sensitive to the value commitments and informed choices of the individual patient. The pre-eminent ethical claims upon health care professionals must not be obscured by the putative demands of scientific development. In view of this it is necessary to re-examine both the general allocation of resources within the health service and legal control of current medical practice in relation to decision making at the 'edges of life' and the requirement of informed consent to treatment. In sum it is argued that any assessment of the health care system and of the relevant law which focuses on the rights of the patient must be both consistent and wide-ranging.

The patient's right to know--a comparative law perspective.

Since every person has the right to determine what will be done to his or her body, he or she has the right to decide whether or not to undergo medical treatment. If this decision is to be more than a pure formality, the patient needs to be fully informed of what that decision entails, and so has a right to know of the risks involved in the treatment he or she is considering. A physician has a corresponding duty to impart the information which the patient needs to enable him or her to reach such an informed decision. This article traces developments in common-law and civil law jurisdictions and considers the extent to which they protect the patient's right to know. The comparative law analysis reveals that English law has tended to fall behind both its common-law relatives and its European neighbours in the amount of protection it affords to this fundamental right because it has allowed liability to be determined by a negligence standard which treats a physician's conformity with the practice of a body of medical opinion as conclusive evidence that he or she has discharged his or her duty. The article warns of a further threat to the patient's right to make an informed decision which has arisen in other common-law jurisdictions in the guise of the so-called 'reasonable patient', whose abstract nature means that his or her presence in standard of care and causation questions brings with it an evidential void which tends to be filled by the evidence of medical experts so that a physician may, once again, be relieved from liability even though he or she has failed to disclose information that the patient before him or her needed to know for the purposes of a treatment decision. The conclusion to be drawn is that only where the standard of care is based on the needs of each patient rather than the opinion of a body of doctors, and only where the focus is kept on the actual patient rather than the hypothetical 'reasonable patient' is the patient's right to know properly protected.

Developing ethical public policy on reproduction and prenatal research: whose interests deserve what protection?

Have physicians and medical researchers begun to play God? Many procedures, including in vitro fertilization, involve treating and transferring embryos: this constitutes experimentation on human beings without the capacity to consent. Will medical ethics meet an increasing societal commitment towards ever greater respect and protection of human life from non-therapeutic experimentation? The medico-ethical aspects of this sensitive and complex issue are examined in detail.

[Medical responsibility for disclosure in legal cases of the German federal court]. / Arztliche Aufklärungspflicht in der Rechtsprechung des Bundesgerichtshofes.

The principles herein discussed show yet again that in determining the physician's duty of disclosure, courts rely on general standards and statutory provisions which they then apply more particularly to the facts of the individual case. Physicians, however, are apprehensive of such flexibel criteria, and perhaps even prejudiced against "the lawyers" who, rather than directing their attention to the needs of the individual doctor-patient relationship, tend to think in terms of the principles involved. To quote a distinguished English judge, "It is always easy to be wise after the event". This, of course, is one thing the physician cannot afford to be. Although courts may have the benefit of hindsight, a physician must assess the patient's informational needs at the outset: a problem he has to learn to live with and for which the lawyer must develop a greater understanding. But in so doing, the lawyer must not lose sight of the patient, who is at the mercy of the physician and can easily fall victim to his lack of diligence. In summary, in defining the extent of the physician's duty to inform, particularly in respect of possible or as yet unknown side effects, the general standards referred to above must be applied, bearing in mind the facts of the individual case, such as the urgency of the proposed treatment, its severity and inherent risks, possible side effects, and the patient's educational background, as well as the possible effect of disclosure on his mental and emotional well-being.