The European Clozapine Task Force is a group of psychiatrists and pharmacologists practicing in 18 countries under European Medicines Agency (EMA) regulation, who are deeply concerned about the underuse of clozapine in European countries. Although clozapine is the most effective antipsychotic for people with treatment-resistant schizophrenia, a large proportion of them do not have access to this treatment. Concerns about clozapine-induced agranulocytosis and stringent blood monitoring rules are major barriers to clozapine prescribing and use. There is a growing body of evidence that the incidence of clozapine-induced agranulocytosis is very low after the first year of treatment. Maintaining lifelong monthly blood monitoring after this period contributes to unjustified discontinuation of clozapine. We leverage recent and replicated evidence on the long-term safety of clozapine to call for the revision and updating of the EMA’s blood monitoring rules, thus aiming to overcome this major barrier to clozapine prescribing and use. We believe the time has come for relaxing the rules without increasing the risks for people using clozapine in Europe.

Burden of bacteraemia is rising due to increased average life expectancy in developed countries. This study aimed to compare the epidemiology and outcomes of bacteraemia in two similarly ageing populations with different ethnicities in Singapore and Denmark. Historical cohorts from the second largest acute-care hospital in Singapore and in the hospitals of two Danish regions included patients aged 15 and above who were admitted from 1 January 2006 to 31 December 2016 with at least 1 day of hospital stay and a pathogenic organism identified. Among 13 144 and 39 073 bacteraemia patients from Singapore and Denmark, similar 30-day mortality rates (16.5%; 20.3%), length of hospital stay (median 14 (IQR: 9–28) days; 11 (6–21)), and admission rate to ICU (15.5%; 15.6%) were observed, respectively. Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus ranked among the top four in both countries. However, Singaporeans had a higher proportion of patients with diabetes (46.8%) and renal disease (29.5%) than the Danes (28.0% and 13.7%, respectively), whilst the Danes had a higher proportion of patients with chronic pulmonary disease (18.0%) and malignancy (35.3%) than Singaporeans (9.7% and 16.2%, respectively). Our study showed that top four causative organisms and clinical outcomes were similar between the two cohorts despite pre-existing comorbidities differed.

Naturally acquired immunity to the different types of malaria in humans occurs in areas of endemic transmission and results in asymptomatic infection of peripheral blood. The current study examined the possibility of naturally acquired immunity in Bornean orangutans, Pongo pygmaeus, exposed to endemic Plasmodium pitheci malaria. A total of 2140 peripheral blood samples were collected between January 2017 and December 2022 from a cohort of 135 orangutans housed at a natural forested Rescue and Rehabilitation Centre in West Kalimantan, Indonesia. Each individual was observed for an average of 4.3 years during the study period. Blood samples were examined by microscopy and polymerase chain reaction for the presence of plasmodial parasites. Infection rates and parasitaemia levels were measured among age groups and all 20 documented clinical malaria cases were reviewed to estimate the incidence of illness and risk ratios among age groups. A case group of all 17 individuals that had experienced clinical malaria and a control group of 34 individuals having an event of >2000 parasites μL−1 blood but with no outward or clinical sign of illness were studied. Immature orangutans had higher-grade and more frequent parasitaemia events, but mature individuals were more likely to suffer from clinical malaria than juveniles. The case orangutans having patent clinical malaria were 256 times more likely to have had no parasitaemia event in the prior year relative to asymptomatic control orangutans. The findings are consistent with rapidly acquired immunity to P. pitheci illness among orangutans that wanes without re-exposure to the pathogen.

The aim of this study was to assess whether adding Ca2+ to aggregate or native forms of β-lactoglobulin alters gut hormone secretion, gastric emptying rates and energy intake in healthy men and women. Fifteen healthy adults (mean ± sd: 9M/6F, age: 24 ± 5 years) completed four trials in a randomised, double-blind, crossover design. Participants consumed test drinks consisting of 30 g of β-lactoglobulin in a native form with (NATIVE + MINERALS) and without (NATIVE) a Ca2+-rich mineral supplement and in an aggregated form both with (AGGREG + MINERALS) and without the mineral supplement (AGGREG). Arterialised blood was sampled for 120 min postprandially to determine gut hormone concentrations. Gastric emptying was determined using 13C-acetate and 13C-octanoate, and energy intake was assessed with an ad libitum meal at 120 min. A protein × mineral interaction effect was observed for total glucagon-like peptide-1 (GLP-1TOTAL) incremental AUC (iAUC; P < 0·01), whereby MINERALS + AGGREG increased GLP-1TOTAL iAUC to a greater extent than AGGREG (1882 ± 603 v. 1550 ± 456 pmol·l−1·120 min, P < 0·01), but MINERALS + NATIVE did not meaningfully alter the GLP-1 iAUC compared with NATIVE (1669 ± 547 v. 1844 ± 550 pmol·l−1·120 min, P = 0·09). A protein × minerals interaction effect was also observed for gastric emptying half-life (P < 0·01) whereby MINERALS + NATIVE increased gastric emptying half-life compared with NATIVE (83 ± 14 v. 71 ± 8 min, P < 0·01), whereas no meaningful differences were observed between MINERALS + AGGREG v. AGGREG (P = 0·70). These did not result in any meaningful changes in energy intake (protein × minerals interaction, P = 0·06). These data suggest that the potential for Ca2+ to stimulate GLP-1 secretion at moderate protein doses may depend on protein form. This study was registered at clinicaltrials.gov (NCT04659902).

The European Food Safety Authority has suggested that EU countries implement the 2 × 24 h diet recall (2 × 24 h DR) method and physical activity (PA) measurements for national dietary surveys. Since 2000, Denmark has used 7 d food diaries (7 d FD) with PA questionnaires and measurements. The accuracy of the reported energy intakes (EI) from the two diet methods, pedometer-determined step counts and self-reported time spent in moderate-to-vigorous PA (MVPA) were compared with total energy expenditure measured by the doubly labelled water (TEEDLW) technique and with PA energy expenditure (PAEE), respectively. The study involved fifty-two male and sixty-eight female volunteers aged 18–60 years who were randomly assigned to start with either the 24 h DR or the web-based 7 d FD, and wore a pedometer for the first 7 d and filled in a step diary. The mean TEEDLW (11·5 MJ/d) was greater than the mean reported EI for the 7 d FD (9·5 MJ/d (P < 0·01)) but the same as the 2 × 24 h DR (11·5 MJ/d). The proportion of under-reporters was 34 % (7 d FD) and 4 % (2 × 24 h DR). Most participants preferred the 7 d DR as it was more flexible, despite altering their eating habits. Pearson’s correlation between steps corrected for cycling and PAEE was r = 0·44, P < 0·01. Spearman’s correlation for self-reported hours spent in MVPA and PAEE was r = 0·58, P < 0·01. The 2 × 24 h DR performs better than the existing 7 d FD method. Pedometer-determined steps and self-reported MVPA are good predictors of PAEE in adult Danes.

Textual data are plagued by underreporting bias. For example, news sources often fail to report human rights violations. Cook et al. propose a multi-source estimator to gauge, and to account for, the underreporting of state repression events within human codings of news texts produced by the Agence France-Presse and Associated Press. We evaluate this estimator with Monte Carlo experiments, and then use it to compare the prevalence and seriousness of underreporting when comparable texts are machine coded and recorded in the World-Integrated Crisis Early Warning System dataset. We replicate Cook et al.’s investigation of human-coded state repression events with our machine-coded events, and validate both models against an external measure of human rights protections in Africa. We then use the Cook et al. estimator to gauge the seriousness and prevalence of underreporting in machine and human-coded event data on human rights violations in Colombia. We find in both applications that machine-coded data are as valid as human-coded data.

A carpeted roller applicator and broadcast sprayer were compared for application of glyphosate, metsulfuron, and picloram to control duncecap and tall larkspur on mountain range sites in southern Idaho and central Utah, respectively. Glyphosate was the most effective herbicide, controlling 96% of both larkspur species when applied by the sprayer and 78% when applied by the roller. There was no difference in larkspur control between application methods using metsulfuron or picloram. Application of herbicides by the carpeted roller was less detrimental to forbs compared to the sprayer, and the roller application of glyphosate did not reduce grass cover. Grass cover doubled following treatments with picloram and metsulfuron.

We tested the applicability of the “passive sampling” hypothesis and theory of island biogeography (TIB) for explaining the diversity of forest-dwelling carabid assemblages (Carabidae: Coleoptera) on 30 forested islands (0.2–980.7 ha) in Lac la Ronge and the adjacent mainland in Saskatchewan, Canada. Species richness per unit area increased with distance to mainland with diversity being highest on the most isolated islands. We detected neither a positive species-area relationship, nor significant differences in species richness among island size classes, or between islands and the mainland. Nonetheless, carabid assemblages distinctly differed on islands <1 ha in area and gradually approached the structure of mainland assemblages as island area increased. Small islands were characterised by abundant populations of small-bodied, winged species and few if any large-bodied, flightless species like Carabus taedatus Fabricius. Our findings suggest that neither the “passive sampling” hypothesis nor the theory of island biogeography adequately explain carabid beetle diversity patterns observed among islands in Lac la Ronge. Instead, we hypothesise that population processes such as higher extinction rates of large-bodied, flightless species and the associated release of smaller-bodied, flying species from intra-guild predation on small islands contribute to observed differences in the structure of carabid assemblages between islands.

The extent of isoleucine epimerization in a calcite speleothem was determined to evaluate the amino acid racemization method in abiotic calcite. A 5.5-cm-thick flowstone slab from Hamarnesgrotta, northern Norway, was analyzed for amino acid concentration, composition, and isoleucine epimerization at 26 levels through the sequence. U-series dates provide an independent chronologic control. Epimerization increases monotonically with stratigraphic depth and linearily with U-series age, independent of amino acid concentrations. The rate of epimerization is calibrated against the U-series dates, and extrapolation into lower strata beyond the U-series limit yields absolute age estimates that are consistent with paleomagnetic data from the same speleothem. The results suggest that, if adequately calibrated, amino acid dating is applicable to speleothem material reaching time spans beyond the range of conventional dating methods. Amino acids in the speleothem were probably derived from surface soils and are associated with brown humic stains in the calcite.

We analyzed birth order differences in means and variances of height and body mass index (BMI) in monozygotic (MZ) and dizygotic (DZ) twins from infancy to old age. The data were derived from the international CODATwins database. The total number of height and BMI measures from 0.5 to 79.5 years of age was 397,466. As expected, first-born twins had greater birth weight than second-born twins. With respect to height, first-born twins were slightly taller than second-born twins in childhood. After adjusting the results for birth weight, the birth order differences decreased and were no longer statistically significant. First-born twins had greater BMI than the second-born twins over childhood and adolescence. After adjusting the results for birth weight, birth order was still associated with BMI until 12 years of age. No interaction effect between birth order and zygosity was found. Only limited evidence was found that birth order influenced variances of height or BMI. The results were similar among boys and girls and also in MZ and DZ twins. Overall, the differences in height and BMI between first- and second-born twins were modest even in early childhood, while adjustment for birth weight reduced the birth order differences but did not remove them for BMI.

Dietary advanced glycation end products (AGE) formed during heating of food have gained interest as potential nutritional toxins with adverse effects on inflammation and glucose metabolism. In the present study, we investigated the short-term effects of high and low molecular weight (HMW and LMW) dietary AGE on insulin sensitivity, expression of the receptor for AGE (RAGE), the AGE receptor 1 (AGER1) and TNF-α, F2-isoprostaglandins, body composition and food intake. For 2 weeks, thirty-six Sprague–Dawley rats were fed a diet containing 20 % milk powder with different proportions of this being given as heated milk powder (0, 40 or 100 %), either native (HMW) or hydrolysed (LMW). Gene expression of RAGE and AGER1 in whole blood increased in the group receiving a high AGE LMW diet, which also had the highest urinary excretion of the AGE, methylglyoxal-derived hydroimidazolone 1 (MG-H1). Urinary excretion of Nε-carboxymethyl-lysine increased with increasing proportion of heat-treated milk powder in the HMW and LMW diets but was unrelated to gene expression. There was no difference in insulin sensitivity, F2-isoprostaglandins, food intake, water intake, body weight or body composition between the groups. In conclusion, RAGE and AGER1 expression can be influenced by a high AGE diet after only 2 weeks in proportion to MG-H1 excretion. No other short-term effects were observed.

A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.