Safety, pharmacokinetics, and pharmacodynamics of efzimfotase alfa, a second-generation enzyme replacement therapy: phase 1, dose-escalation study in adults with hypophosphatasia.

Hypophosphatasia (HPP) is a rare, inherited metabolic disease caused by deficient activity of tissue-nonspecific alkaline phosphatase (TNSALP). Efzimfotase alfa (ALXN1850) is a second-generation TNSALP enzyme replacement therapy in development for HPP. This first-in-human open-label, dose-escalating phase 1 trial evaluated efzimfotase alfa safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity. Fifteen adults (5/cohort) with HPP received efzimfotase alfa in doses of 15 mg (cohort 1), 45 mg (cohort 2), or 90 mg (cohort 3) as one intravenous (i.v.) dose followed by 3 weekly subcutaneous (s.c.) doses. The primary objective was to assess safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics of ALP substrates known to be biomarkers of disease (inorganic pyrophosphate [PPi] and pyridoxal 5'-phosphate [PLP]) and immunogenicity. Treatment-emergent adverse events (TEAEs) occurred in 12 (80%) participants. Eight (53%) participants had injection site reactions (ISRs), observed after 10 of 41 (24%) s.c. injections. Most ISR TEAEs were mild and resolved within 1-2 d. Peak and total exposures of efzimfotase alfa increased in a greater-than-dose proportional manner over the range of 15-90 mg after i.v. and s.c. dosing. The arithmetic mean elimination half-life was approximately 6 d; absolute bioavailability was 28.6%-36.8% over the s.c. dose range of 15-90 mg. Dose-dependent reductions in plasma concentrations of PPi and PLP relative to baseline reached nadir in the first week after i.v. dosing and were sustained for 3-4 wk after the last s.c. dose. Four (27%) participants tested positive for antidrug antibodies (ADAs), 3 of whom were ADA positive before the first dose of efzimfotase alfa. ADAs had no apparent effect on efzimfotase alfa pharmacokinetics/pharmacodynamics. No participants had neutralizing antibodies. Efzimfotase alfa demonstrated acceptable safety, tolerability, and pharmacokinetic profiles and was associated with sustained reductions in biomarkers of disease in adults with HPP, supporting further evaluation in adult and pediatric patients. Registration: ClinicalTrials.gov NCT04980248 (https://clinicaltrials.gov/study/NCT04980248).

Hypophosphatasia (HPP) is a rare metabolic disease caused by low activity of tissue nonspecific alkaline phosphatase (TNSALP), which is an enzyme involved in the formation and healing of bone and function of other body systems. People with HPP experience fractures, difficulty moving and walking, muscle weakness, pain, fatigue (tiredness), and teeth problems. Babies with HPP often have life-threatening breathing problems, craniosynostosis (early closure of skull bones), seizures that respond to treatment with vitamin B6, failure to thrive (inability to gain weight), and weak and abnormally shaped bones. Enzyme replacement therapy (ERT) for HPP was developed to supplement defective TNSALP with active enzyme, thus improving bone health and the symptoms of HPP. Asfotase alfa, the first ERT approved for the treatment of HPP, is given by subcutaneous injection either 3 or 6 times per week. Efzimfotase alfa is a second-generation ERT that is being developed for the treatment of HPP. Although similar to asfotase alfa, efzimfotase alfa has incorporated several changes that have the potential to require lower doses and reduce injection volume and dosing frequency, thereby potentially improving the treatment experience for patients. This first-in-human study investigated the safety, tolerability, pharmacokinetics (how a drug is absorbed into, distributed throughout, and removed from the body), pharmacodynamics (effects of the drug within the body), and immunogenicity (ability of a drug to provoke an undesirable immune response) of 4 injections of efzimfotase alfa when given by intravenous and subcutaneous routes of administration to adults with HPP. Our results showed that efzimfotase alfa has acceptable safety and pharmacokinetics and is effective for reducing biomarkers (measurable substances that reflect underlying disease) when given once weekly by subcutaneous injection, supporting further evaluation of efzimfotase alfa in planned clinical trials in adult and pediatric patients with HPP.

Variation in placentophagy in golden snub-nosed monkeys (Rhinopithecus roxellana) reflects nutritional constraints.

Golden snub-nosed monkeys show inconsistent frequency of placentophagy between wild and captive populations, with almost all births in the wild but around half of the births in captivity accompanied by the female's consumption of placenta. This aligns with nutritional demands-driven placentophagy, as captive populations are generally under less nutritional constraints for breeding females than the wild population. Placentophagy is probably adaptive in the wild and under positive selection due to nutritional benefits to both mothers and infants.

How to Effectively Reduce Honey Adulteration in China: An Analysis Based on Evolutionary Game Theory.

Apiculture has been greatly developed in recent years in China. Beekeeping cooperatives and honey manufacturing enterprises have increased rapidly. As a result, a variety of honey products have entered the market, adding vitality to the food economy; however, the adulteration of honey products is on the rise in China. Previous attempts to control the adulteration of honey products mostly relied on technical, product-specific measures, and there was a lack of modeling research to guide the supervision of the honey product industry. In order to help local governments to better control the adulteration of honey products from a management perspective, this paper establishes an evolutionary game model composed of beekeeping cooperatives, honey product enterprises, and local governments. Through stability analysis and model simulation, we found that local government subsidies to cooperatives have little impact on the game system. Local government penalties to cooperatives and price adjustments of unadulterated raw honey by cooperatives are effective management tools to reduce the adulteration behavior of cooperatives. Local government penalties for enterprises are an effective management tool to reduce the adulteration behavior of enterprises. This research provides useful information for government agencies to design appropriate policies/business modes so as to promote sustainability and the healthy development of the honey product industry in China.

Intravenous ravulizumab in mechanically ventilated patients hospitalised with severe COVID-19: a phase 3, multicentre, open-label, randomised controlled trial.

BACKGROUND: The complement pathway is a potential target for the treatment of severe COVID-19. We evaluated the safety and efficacy of ravulizumab, a terminal complement C5 inhibitor, in patients hospitalised with severe COVID-19 requiring invasive or non-invasive mechanical ventilation. METHODS: This phase 3, multicentre, open-label, randomised controlled trial (ALXN1210-COV-305) enrolled adult patients (aged ≥18 years) from 31 hospitals in France, Japan, Spain, the UK, and the USA. Eligible patients had a confirmed diagnosis of SARS-CoV-2 that required hospitalisation and either invasive or non-invasive mechanical ventilation, with severe pneumonia, acute lung injury, or acute respiratory distress syndrome confirmed by CT scan or x-ray. We randomly assigned participants (2:1) to receive intravenous ravulizumab plus best supportive care (BSC) or BSC alone using a web-based interactive response system. Randomisation was in permuted blocks of six with stratification by intubation status. Bodyweight-based intravenous doses of ravulizumab were administered on days 1, 5, 10, and 15. The primary efficacy endpoint was survival based on all-cause mortality at day 29 in the intention-to-treat (ITT) population. Safety endpoints were analysed in all randomly assigned patients in the ravulizumab plus BSC group who received at least one dose of ravulizumab, and in all randomly assigned patients in the BSC group. The trial is registered with ClinicalTrials.gov, NCT04369469, and was terminated at interim analysis due to futility. FINDINGS: Between May 10, 2020, and Jan 13, 2021, 202 patients were enrolled in the study and randomly assigned to ravulizumab plus BSC or BSC. 201 patients were included in the ITT population (135 in the ravulizumab plus BSC group and 66 in the BSC group). The ravulizumab plus BSC group comprised 96 (71%) men and 39 (29%) women with a mean age of 63·2 years (SD 13·23); the BSC group comprised 43 (65%) men and 23 (35%) women with a mean age of 63·5 years (12·40). Most patients (113 [84%] of 135 in the ravulizumab plus BSC group and 53 [80%] of 66 in the BSC group) were on invasive mechanical ventilation at baseline. Overall survival estimates based on multiple imputation were 58% for patients receiving ravulizumab plus BSC and 60% for patients receiving BSC (Mantel-Haenszel analysis: risk difference -0·0205; 95% CI -0·1703 to 0·1293; one-sided p=0·61). In the safety population, 113 (89%) of 127 patients in the ravulizumab plus BSC group and 56 (84%) of 67 in the BSC group had a treatment-emergent adverse event. Of these events, infections and infestations (73 [57%] vs 24 [36%] patients) and vascular disorders (39 [31%] vs 12 [18%]) were observed more frequently in the ravulizumab plus BSC group than in the BSC group. Five patients had serious adverse events considered to be related to ravulizumab. These events were bacteraemia, thrombocytopenia, oesophageal haemorrhage, cryptococcal pneumonia, and pyrexia (in one patient each). INTERPRETATION: Addition of ravulizumab to BSC did not improve survival or other secondary outcomes. Safety findings were consistent with the known safety profile of ravulizumab in its approved indications. Despite the lack of efficacy, the study adds value for future research into complement therapeutics in critical illnesses by showing that C5 inhibition can be accomplished in severely ill patients. FUNDING: Alexion, AstraZeneca Rare Disease.

Social and paternal female choice for male MHC genes in golden snub-nosed monkeys (Rhinopithecus roxellana).

Genes of the major histocompatibility complex (MHC) play important roles in vertebrate immunocompetence. MHC genes thus offer females indirect benefits to mate choice through the production of offspring of an optimal MHC genotype. Females may choose males with specific MHC haplotypes, dissimilar MHC genotypes, MHC heterozygous males or MHC-diverse males. We tested these four alternatives for both female social and paternal choice in wild golden snub-nosed monkeys (Rhinopithecus roxellana) by examining overall genetic variability (via microsatellites) and four MHC-genes (DRB1, DRB2, DQA1 and DQB1). Monte Carlo randomization tests showed that MHC dissimilarity was favoured for social choice (males to which females were socially affiliated) and intermediate MHC dissimilarity was favoured in paternal choice (fathers of offspring). No evidence of inbreeding avoidance was found for either social or paternal mates. We found that MHC heterozygotes, higher microsatellite multilocus heterozygosity and higher microsatellites diversity were favoured for social mates, and higher microsatellite diversity was favoured for paternal mates. Independent of male age, we found that the formation of male-female social pairings is significantly predicted by compatibility based on the sharing of MHC haplotypes. However, we found no evidence of independent genetic effects on the duration of male-female social pairings, male social status (achieving OMU leader male status or not), the number of females with which individual leader males paired, the likelihood of potential male-female pairings producing offspring, or whether males fathered offspring or not. Overall, our findings suggest different genetic factors are involved in social and paternal choice in R. roxellana.

Do golden snub-nosed monkeys use deceptive alarm calls during competition for food?

Tactical deception can be beneficial for social animals during intra-specific competition. However, the use of tactical deception in wild mammals is predicted to be rare. We tested whether a food-provisioned free-ranging band of golden snub-nosed monkeys (Rhinopithecus roxellana) use alarm calls in a functionally deceptive manner to gain access to food resources, whether the rate of deceptive alarm calls varies among individuals, and whether there are any counter-deception behaviors. We used a hexagonal camera array consisting of 10 cameras to record videos during feeding, which allowed us to identify individual alarm callers. We found evidence that these monkeys use deceptive alarms and that adult females were more likely to use such calls than other individuals. The monkeys increased their rates of response to alarm calls when competition for food was high. However, we found no direct evidence of any counter-deception strategies.

vcfpop: Performing population genetics analyses for autopolyploids and aneuploids based on next-generation sequencing data sets.

Polyploids are cells or organisms with a genome consisting of more than two sets of homologous chromosomes. Polyploid plants have important traits that facilitate speciation and are thus often model systems for evolutionary, molecular ecology and agricultural studies. However, due to their unusual mode of inheritance and double-reduction, diploid models of population genetic analysis cannot properly be applied to autopolyploids. To overcome this problem, we developed a software package entitled vcfpop to perform a variety of population genetic analyses for autopolyploids, such as parentage analysis, analysis of molecular variance, principal coordinates analysis, hierarchical clustering analysis and Bayesian clustering. We used three data sets to evaluate the capability of vcfpop to analyse large data sets on a desktop computer. This software is freely available at http://github.com/huangkang1987/vcfpop.

Complement blockade with eculizumab for treatment of severe Coronavirus Disease 2019 in pregnancy: A case series.

PROBLEM: We evaluated eculizumab, a complement protein C5 inhibitor, for treatment of severe COVID-19 in pregnant and postpartum individuals. METHOD OF STUDY: Protocol ECU-COV-401 (clinicaltrials.gov NCT04355494) is an open label, multicenter, Expanded Access Program (EAP), evaluating eculizumab for treatment of severe COVID-19. Participants enrolled at our center from August 2020 to February 2021. Hospitalized patients were eligible if they had severe COVID-19 with bilateral pulmonary infiltrates and oxygen requirement. Eculizumab was administered on day 1 (1200 mg IV) with additional doses if still hospitalized (1200 mg IV on Days 4 and 8; 900 mg IV on Days 15 and 22; optional doses on Days 12 and 18). The primary outcome was survival at Day 15. Secondary outcomes included survival at Day 29, need for mechanical ventilation, and duration of hospital stay. We evaluated pharmacokinetic and pharmacodynamic data, safety, and adverse outcomes. RESULTS: Eight participants were enrolled at the Cedars-Sinai Medical Center, six during pregnancy (mean 30 ± 4.0 weeks) and two in the postpartum period. Baseline oxygen requirement ranged from 2 L/min nasal cannula to 12 L/min by non-rebreather mask. The median number of doses of eculizumab was 2 (range 1-3); the median time to hospital discharge was 5.5 days (range 3-12). All participants met the primary outcome of survival at Day 15, and all were alive and free of mechanical ventilation at Day 29. In three participants we demonstrated that free C5 and soluble C5b-9 levels decreased following treatment. There were no serious adverse maternal or neonatal events attributed to eculizumab at 3 months. CONCLUSION: We describe use of eculizumab to treat severe COVID-19 in a small series of pregnant and postpartum adults. A larger, controlled study in pregnancy is indicated.

Specialized digestive adaptations within the hindgut of a colobine monkey.

In mammal herbivores, fiber digestion usually occurs predominantly in either the foregut or the hindgut. Reports of mechanisms showing synergistic function in both gut regions for the digestion of fiber and other nutrients in wild mammals are rare because it requires integrative study of anatomy, physiology, and gut microbiome. Colobine monkeys (Colobinae) are folivorous, with high-fiber foods fermented primarily in their foreguts. A few colobine species live in temperate regions, so obtaining energy from fiber during the winter is essential. However, the mechanisms enabling this remain largely unknown. We hypothesized that such species possess specialized mechanisms to enhance fiber digestion in the hindgut and studied microbial and morphological digestive adaptations of golden snub-nosed monkeys (GSMs), Rhinopithecus roxellana. which is a temperate forest colobine from central China that experiences high-thermal-energy demands while restricted to a fibrous, low-energy winter diet. We tested for synergistic foregut and hindgut fiber digestion using comparisons of morphology, microbiome composition and function, and digestive efficiency. We found that the GSM colon has a significantly greater volume than that of other foregut-fermenting colobines. The microbiomes of the foregut and hindgut differed significantly in composition and abundance. However, while digestive efficiency and the expression of microbial gene functions for fiber digestion were higher in the foregut than in the hindgut, both gut regions were dominated by microbial taxa producing enzymes to enable active digestion of complex carbohydrates. Our data suggest that both the GSM foregut and hindgut facilitate fiber digestion and that an enlarged colon is likely an adaptation to accommodate high throughput of fiber-rich food during winter.