Drawing on ethical and legal frameworks in the Netherlands, the United States and France, we examine whether physicians are expected to inform patients about potentially relevant opportunities for expanded access to investigational drugs. While we found no definitive legal obligation, we argue that physicians have a moral obligation to discuss opportunities for expanded access with patients who have run out of treatment options to prevent inequality, to promote autonomy, and to achieve beneficence.

Higher milk intake has been associated with a lower stroke risk, but not with risk of CHD. Residual confounding or reverse causation cannot be excluded. Therefore, we estimated the causal association of milk consumption with stroke and CHD risk through instrumental variable (IV) and gene-outcome analyses. IV analysis included 29 328 participants (4611 stroke; 9828 CHD) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD (eight European countries) and European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) case-cohort studies. rs4988235, a lactase persistence (LP) SNP which enables digestion of lactose in adulthood was used as genetic instrument. Intake of milk was first regressed on rs4988235 in a linear regression model. Next, associations of genetically predicted milk consumption with stroke and CHD were estimated using Prentice-weighted Cox regression. Gene-outcome analysis included 777 024 participants (50 804 cases) from MEGASTROKE (including EPIC-CVD), UK Biobank and EPIC-NL for stroke, and 483 966 participants (61 612 cases) from CARDIoGRAM, UK Biobank, EPIC-CVD and EPIC-NL for CHD. In IV analyses, each additional LP allele was associated with a higher intake of milk in EPIC-CVD (β = 13·7 g/d; 95 % CI 8·4, 19·1) and EPIC-NL (36·8 g/d; 95 % CI 20·0, 53·5). Genetically predicted milk intake was not associated with stroke (HR per 25 g/d 1·05; 95 % CI 0·94, 1·16) or CHD (1·02; 95 % CI 0·96, 1·08). In gene-outcome analyses, there was no association of rs4988235 with risk of stroke (OR 1·02; 95 % CI 0·99, 1·05) or CHD (OR 0·99; 95 % CI 0·95, 1·03). Current Mendelian randomisation analysis does not provide evidence for a causal inverse relationship between milk consumption and stroke or CHD risk.

Coronavirus disease 2019 (Covid-19), caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2, exerts far-reaching effects on public health and socio-economic welfare. The majority of infected individuals have mild to moderate symptoms, but a significant proportion develops respiratory failure due to pneumonia. Thrombosis is another frequent manifestation of Covid-19 that contributes to poor outcomes. Vitamin K plays a crucial role in the activation of both pro- and anticlotting factors in the liver and the activation of extrahepatically synthesised protein S which seems to be important in local thrombosis prevention. However, the role of vitamin K extends beyond coagulation. Matrix Gla protein (MGP) is a vitamin K-dependent inhibitor of soft tissue calcification and elastic fibre degradation. Severe extrahepatic vitamin K insufficiency was recently demonstrated in Covid-19 patients, with high inactive MGP levels correlating with elastic fibre degradation rates. This suggests that insufficient vitamin K-dependent MGP activation leaves elastic fibres unprotected against SARS-CoV-2-induced proteolysis. In contrast to MGP, Covid-19 patients have normal levels of activated factor II, in line with previous observations that vitamin K is preferentially transported to the liver for activation of procoagulant factors. We therefore expect that vitamin K-dependent endothelial protein S activation is also compromised, which would be compatible with enhanced thrombogenicity. Taking these data together, we propose a mechanism of pneumonia-induced vitamin K depletion, leading to a decrease in activated MGP and protein S, aggravating pulmonary damage and coagulopathy, respectively. Intervention trials should be conducted to assess whether vitamin K administration plays a role in the prevention and treatment of severe Covid-19.

This study investigated bidirectional associations between intake of food groups and depressive symptoms in 1058 Italian participants (aged 20–102 years) of the Invecchiare in Chianti study. Dietary intake, assessed with a validated FFQ, and depressive symptoms, measured with the Center for Epidemiologic Studies Depression scale (CES-D), were assessed at baseline and after 3, 6 and 9 years. Associations of repeated measurements of intakes of thirteen food groups with 3-year changes in depressive symptoms, and vice versa, were analysed using linear mixed models and logistic generalised estimating equations. Fish intake was inversely (quartile (Q)4 v. Q1, B=–0·97, 95 % CI –1·74, –0·21) and sweet food intake positively (Q4 v. Q1, B=1·03, 95 % CI 0·25, 1·81) associated with subsequent CES-D score. In the other direction, higher CES-D scores were associated with decreases in intakes of vegetables (ratio: 0·995, 95 % CI 0·990, 0·999) and red and processed meat (B=–0·006, 95 % CI –0·010, –0·001), an increase in dairy product intake (ratio: 1·008, 95 % CI 1·004, 1·013), and increasing odds of eating savoury snacks (OR: 1·012, 95 % CI 1·000, 1·024). Fruit, nuts and legumes, potatoes, wholegrain bread, olive oil, sugar-sweetened beverages, and coffee and tea were not significantly associated in either direction. Our study confirmed bidirectional associations between food group intakes and depressive symptoms. Fish and sweet food intakes were associated with 3-year improvement and deterioration in depressive symptoms, respectively. Depressive symptoms were associated with 3-year changes in vegetable, meat, dairy product and savoury snack intakes. Trials are necessary to examine the causal associations between food groups and depression.

Högbomite is reported from two upper-amphibolite and granulite-facies, sapphirine-bearing, Al–Mg–Fe-rich and silica-poor lens-shaped layers within the Bamble Sector, south Norway. Primary assemblages, indicating peak metamorphic conditions of 773-844°C at 7 kbar (Mg–Fe exchange thermometry), are spinel–sapphirine–biotite–gedrite, spinel–corundum–sapphirine–cordierite and orthopyroxene–biotite–cordierite–plagioclase. Högbomite formed by hydrous alteration and oxidation of primary spinel and rutile and/or ilmenite according to the generalised reaction:

Suggested conditions of högbomite formation are 550–620°C and 6–7 kbar. The högbomites contain 10.2–14.7 wt.% MgO, 04).3 wt.% ZnO, 58.9–62.1 wt.% Al2O3 and 15.6-17.6 wt.% Fe as FeO. The two högbomite may belong to different polytypes, as suggested by their differing TiO2 (9.9-10.1 versus 5.7–5.8 wt. %) and calculated Fe3+ – and H2O–contents. The partitioning of Zn between spinel and högbomite is not uniform and is considered to depend upon prevailing fo2 and aH2O.

A new framework is presented for estimation and control of instabilities in wall-bounded shear flows described by the linearised Navier–Stokes equations. The control design considers the use of localised actuators/sensors to account for convective instabilities in an ${\mathcal{H}}_{2}$ optimal control framework. External sources of disturbances are assumed to enter the control domain through the inflow. A new inflow disturbance model is proposed for external excitation of the perturbation modes that contribute to transition. This model allows efficient estimation of the flow perturbations within the localised control region of a conceptually unbounded domain. The state-space discretisation of the infinite-dimensional system is explicitly obtained, which allows application of linear control theoretic tools. A reduced-order model is subsequently derived using exact balanced truncation that captures the input/output behaviour and the dominant perturbation dynamics. This model is used to design an ${\mathcal{H}}_{2}$ optimal controller to suppress the instability growth. The two-dimensional non-periodic channel flow is considered as an application case. Disturbances are generated upstream of the control domain and the resulting flow perturbations are estimated/controlled using point wall shear measurements and localised unsteady blowing and suction at the wall. The controller is able to cancel the perturbations and is robust to both unmodelled disturbances and sensor inaccuracies. For single-frequency and multiple-frequency disturbances with low sensor noise a nearly full cancellation is achieved. For stochastic forced disturbances and high sensor noise an energy reduction in perturbation wall shear stress of 96 % is shown.

Methodological aspects of digestibility measurements were studied in four Welsh pony geldings consuming haylage-based diets with increasing proportions of a pelleted concentrate according to a 4×4 Latin square design experiment. Ponies were fed four experimental, iso-energetic (net energy (NE) basis) diets (i.e. 22 MJ NE/day) with increasing proportions of a pelleted concentrate (C) in relation to haylage (H). The absolute amounts of diet dry matter fed per day were 4.48 kg of H (100H), 3.36 and 0.73 kg of H and C (75H25C), 2.24 and 1.45 kg of H and C (50H50C) and 1.12 and 2.17 kg of H and C (25H75C). Diets were supplemented with minerals, vitamins and TiO2 (3.7 g Ti/day). Voluntary voided faeces were quantitatively collected daily during 10 consecutive days and analysed for moisture, ash, ADL, acid-insoluble ash (AIA) and Ti. A minimum faeces collection period of 6 consecutive days, along with a 14-day period to adapt the animals to the diets and become accustomed to the collection procedure, is recommended to obtain accurate estimations on dry matter digestibility and organic matter digestibility (OMD) in equids fed haylage-based diets supplemented with concentrate. In addition, the recovery of AIA, ADL and Ti was determined and evaluated. Mean faecal recovery over 10 consecutive days across diets for AIA, ADL and Ti was 124.9% (SEM 2.9), 108.7% (SEM 2.0) and 97.5% (SEM 0.9), respectively. Cumulative faecal recovery of AIA significantly differed between treatments, indicating that AIA is inadequate to estimate the OMD in equines. In addition, evaluation of the CV of mean cumulative faecal recoveries obtained by AIA, ADL and Ti showed greater variations in faecal excretion of AIA (9.1) and ADL (7.4) than Ti (3.7). The accuracy of prediction of OMD was higher with the use of Ti than ADL. The use of Ti is preferred as a marker in digestibility trials in equines fed haylage-based diets supplemented with increasing amounts of pelleted concentrate.

The aim of any diffraction experiment is to obtain reproducible data of high accuracy and precision so that the data can be correctly interpreted and analyzed. Various methods of sample preparation have been devised so that reproducibility, precision and accuracy can be obtained. The success of a diffraction experiment will often depend on the correct choice of preparation method for the sample being analyzed and for the instrument being used in the analysis.

A diffraction pattern contains three types of useful information: the positions of the diffraction maxima, the peak intensities, and the intensity distribution as a function of diffraction angle. This information can be used to identify and quantify the contents of the sample, as well as to calculate the material's crystallite size and distribution, crystallinity, and stress and strain. The ideal preparation for a given experiment depends largely on information desired.

Mounted police horses have to cope with challenging, unpredictable situations when on duty and it is essential to gain insight into how these horses handle stress to warrant their welfare. The aim of the study was to evaluate physiological and behavioral responses of 12 (six experienced and six inexperienced) police horses during police training. Horses were evaluated during four test settings at three time points over a 7-week period: outdoor track test, street track test, indoor arena test and smoke machine test. Heart rate (HR; beats/min), HR variability (HRV; root means square of successive differences; ms), behavior score (BS; scores 0 to 5) and standard police performance score (PPS; scores 1 to 0) were obtained per test. All data were statistically evaluated using a linear mixed model (Akaike's Information criterium; t > 2.00) or logistic regression (P < 0.05). HR of horses was increased at indoor arena test (98 ± 26) and smoke machine test (107 ± 25) compared with outdoor track (80 ± 12, t = 2.83 and t = 3.91, respectively) and street track tests (81 ± 14, t = 2.48 and t = 3.52, respectively). HRV of horses at the indoor arena test (42.4 ± 50.2) was significantly lower compared with street track test (85.7 ± 94.3 and t = 2.78). BS did not show significant differences between tests and HR of horses was not always correlated with the observed moderate behavioral responses. HR, HRV, PPS and BS did not differ between repetition of tests and there were no significant differences in any of the four tests between experienced and inexperienced horses. No habituation occurred during the test weeks, and experience as a police horse does not seem to be a key factor in how these horses handle stress. All horses showed only modest behavioral responses, and HR may provide complimentary information for individual evaluation and welfare assessment of these horses. Overall, little evidence of stress was observed during these police training tests. As three of these tests (excluding the indoor arena test) reflect normal police work, it is suggested that this kind of police work is not significantly stressful for horses and will have no negative impact on the horse's welfare.