Safety and efficacy of arimoclomol for inclusion body myositis: a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Inclusion body myositis is the most common progressive muscle wasting disease in people older than 50 years, with no effective drug treatment. Arimoclomol is an oral co-inducer of the cellular heat shock response that was safe and well-tolerated in a pilot study of inclusion body myositis, reduced key pathological markers of inclusion body myositis in two in-vitro models representing degenerative and inflammatory components of this disease, and improved disease pathology and muscle function in mutant valosin-containing protein mice. In the current study, we aimed to assess the safety, tolerability, and efficacy of arimoclomol in people with inclusion body myositis. METHODS: This multicentre, randomised, double-blind, placebo-controlled study enrolled adults in specialist neuromuscular centres in the USA (11 centres) and UK (one centre). Eligible participants had a diagnosis of inclusion body myositis fulfilling the European Neuromuscular Centre research diagnostic criteria 2011. Participants were randomised (1:1) to receive either oral arimoclomol 400 mg or matching placebo three times daily (1200 mg/day) for 20 months. The randomisation sequence was computer generated centrally using a permuted block algorithm with randomisation numbers masked to participants and trial staff, including those assessing outcomes. The primary endpoint was the change from baseline to month 20 in the Inclusion Body Myositis Functional Rating Scale (IBMFRS) total score, assessed in all randomly assigned participants, except for those who were randomised in error and did not receive any study medication, and those who did not meet inclusion criteria. Safety analyses included all randomly assigned participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02753530, and is completed. FINDINGS: Between Aug 16, 2017 and May 22, 2019, 152 participants with inclusion body myositis were randomly assigned to arimoclomol (n=74) or placebo (n=78). One participant was randomised in error (to arimoclomol) but not treated, and another (assigned to placebo) did not meet inclusion criteria. 150 participants (114 [76%] male and 36 [24%] female) were included in the efficacy analyses, 73 in the arimoclomol group and 77 in the placebo group. 126 completed the trial on treatment (56 [77%] and 70 [90%], respectively) and the most common reason for treatment discontinuation was adverse events. At month 20, mean IBMFRS change from baseline was not statistically significantly different between arimoclomol and placebo (-3·26, 95% CI -4·15 to -2·36 in the arimoclomol group vs -2·26, -3·11 to -1·41 in the placebo group; mean difference -0·99 [95% CI -2·23 to 0·24]; p=0·12). Adverse events leading to discontinuation occurred in 13 (18%) of 73 participants in the arimoclomol group and four (5%) of 78 participants in the placebo group. Serious adverse events occurred in 11 (15%) participants in the arimoclomol group and 18 (23%) in the placebo group. Elevated transaminases three times or more of the upper limit of normal occurred in five (7%) participants in the arimoclomol group and one (1%) in the placebo group. Tubulointerstitial nephritis was observed in one (1%) participant in the arimoclomol group and none in the placebo group. INTERPRETATION: Arimoclomol did not improve efficacy outcomes, relative to placebo, but had an acceptable safety profile in individuals with inclusion body myositis. This is one of the largest trials done in people with inclusion body myositis, providing data on disease progression that might be used for subsequent clinical trial design. FUNDING: US Food and Drug Administration Office of Orphan Products Development and Orphazyme.

Sustainable pathways towards climate and biodiversity goals in the UK: the importance of managing land-use synergies and trade-offs.

Agricultural and environmental policies are being fundamentally reviewed and redesigned in the UK following its exit from the European Union. The UK government and the Devolved Administrations recognise that current land use is not sustainable and that there is now an unprecedented opportunity to define a better land strategy that responds fully to the interconnected challenges of climate change, biodiversity loss and sustainable development. This paper presents evidence from three pathways (current trends, sustainable medium ambition, and sustainable high ambition) to mid-century that were co-created with UK policymakers. The pathways were applied to a national integrated food and land-use model (the FABLE calculator) to explore potential synergies and trade-offs between achieving multiple sustainability targets under limited land availability and constraints to balance food supply and demand at national and global levels. Results show that under the Current Trends pathway all unprotected open natural land would be converted to urban, agriculture and afforested land, with the consequence that from 2030 onwards tree planting targets could not be met. In contrast, the two sustainable pathways illustrate how dietary change, agricultural productivity improvements and waste reduction can free up land for nature recovery and carbon sequestration. This enables a transition to a sustainable food and land-use system that provides a net carbon sink with up to 44% of land able to support biodiversity conservation. We highlight key trade-offs and synergies, which are important to consider for designing and implementing emerging national policies. These include the strong dependence of climate, food and biodiversity targets on dietary shifts, sustainable improvements in agricultural productivity, improved land-use design for protecting and restoring nature, and rapid reductions in food loss and waste. Supplementary Information: The online version contains supplementary material available at 10.1007/s11625-022-01242-8.

The evolution of quantitative sensitivity.

The ability to represent approximate quantities appears to be phylogenetically widespread, but the selective pressures and proximate mechanisms favouring this ability remain unknown. We analysed quantity discrimination data from 672 subjects across 33 bird and mammal species, using a novel Bayesian model that combined phylogenetic regression with a model of number psychophysics and random effect components. This allowed us to combine data from 49 studies and calculate the Weber fraction (a measure of quantity representation precision) for each species. We then examined which cognitive, socioecological and biological factors were related to variance in Weber fraction. We found contributions of phylogeny to quantity discrimination performance across taxa. Of the neural, socioecological and general cognitive factors we tested, cortical neuron density and domain-general cognition were the strongest predictors of Weber fraction, controlling for phylogeny. Our study is a new demonstration of evolutionary constraints on cognition, as well as of a relation between species-specific neuron density and a particular cognitive ability. This article is part of the theme issue 'Systems neuroscience through the lens of evolutionary theory'.

Perceptions and barriers to the annual influenza vaccine compared with the coronavirus disease 2019 vaccine in an urban underserved population.

BACKGROUND: For a vaccine to be successful, communities must perceive it as important, safe, effective, and necessary. However, there are many barriers and hesitancies to vaccination. Underserved patient populations may face additional challenges related to access and cost. Because community pharmacists improve vaccine access and increase vaccination rates, it is beneficial for pharmacists to understand perceptions and barriers to vaccinations in their community to increase vaccine confidence. OBJECTIVES: This study aims to assess and compare barriers and perceptions of the annual influenza to the coronavirus disease 2019 (COVID-19) vaccine for underserved patients of a charitable pharmacy. METHODS: Patients who qualified to receive medications from an outpatient charitable pharmacy took an electronic survey when receiving medications. The survey incorporated questions developed by the World Health Organization's Strategic Advisory Group of Experts on Vaccine Hesitancy on a 5-point Likert scale. Questions about the influenza and COVID-19 vaccines mirrored one another. Demographic data such as age, race, sex, and education level were also collected. RESULTS: Of the 189 patients surveyed at the charitable pharmacy, 71.7% were 55 years old and older and 58.9% were female. Of note, 78% and 77% of participants agreed or strongly agreed that the influenza and COVID-19 vaccines, respectively, were important for the health of others in their community. Adverse effects and the cost of the COVID-19 vaccine were noted to be statistically significantly more of a concern with the COVID-19 vaccine than that of the influenza vaccine (P < 0.001). CONCLUSION: Ensuring equitable vaccine access, promoting the COVID-19 vaccine as free, and eliciting and addressing individual persons' concerns related to vaccine safety and adverse effects are all important ways pharmacists and other health care providers and community stakeholders can help promote vaccine confidence within the populations they serve.

Identifying Nutrition Risk in a Charitable Pharmacy Population.

While prior research has shown that food insecurity and malnutrition worsen health outcomes and increase health care costs, nutrition risk is rarely assessed in the community setting. Tools exist to screen for food insecurity and malnutrition individually, but none screen for both. This study aimed to implement a dual-purpose screening tool to identify nutrition risk in a community setting, to characterize nutrition risk in a charitable pharmacy population, and to identify patients who screen positive for nutrition risk and connect them to community nutrition resources. Of the 221 patients screened during their initial and annual qualification interview at the Charitable Pharmacy of Central Ohio, 140 (63%) screened positive for nutrition risk. There were 84 (38%) patients positive for food insecurity, 14 (6%) positive for malnutrition risk, and 42 (19%) positive for both. Patients at nutrition risk were referred to nutrition resources, including food pantries, home-delivered meals, and SNAP.

Capillary-channeled polymer (C-CP) fibers for the rapid extraction of proteins from urine matrices prior to detection with MALDI-MS.

PURPOSE: While MS is a powerful tool for biomarker determinations, the high salt content and the small molecules present in urine poses incredible challenges. Separation/extraction methods must be employed for the isolation of target species at relevant concentrations. Micropipette tips packed with capillary-channeled polymer (C-CP) fibers are employed for the SPE of proteins from a synthetic and a certified urine matrix. EXPERIMENTAL DESIGN: Extractions are performed utilizing a very simple centrifugation method to spin-down species through the C-CP fiber tips. Proteins adsorb to the hydrophobic polypropylene fibers and are eluted in a solvent suitable for MALDI-MS analysis. Figures of merit are determined for representative compounds ß2-microglobulin, retinol binding protein, and transferrin. RESULTS: The optimum protein processing included a 100 µL aqueous rinse and an elution solvent composition was 10 µL of 55:45 ACN:water (with triflouroacetic acid). MALDI-MS responses for the target proteins are improved from nondetectable levels to eventually yield LOD ranging from 5 to 180 nM in 1 µL aliquots. CONCLUSION AND CLINICAL RELEVANCE: C-CP fiber tips offer a plethora of advantages including low materials costs, high throughput, microvolume processing, and the determination of sub-nanogram quantities of analyte; allowing determination of biomarkers that are otherwise undetectable in urine matrices.

Lemurs and macaques show similar numerical sensitivity.

We investigated the precision of the approximate number system (ANS) in three lemur species (Lemur catta, Eulemur mongoz, and Eulemur macaco flavifrons), one Old World monkey species (Macaca mulatta) and humans (Homo sapiens). In Experiment 1, four individuals of each nonhuman primate species were trained to select the numerically larger of two visual arrays on a touchscreen. We estimated numerical acuity by modeling Weber fractions (w) and found quantitatively equivalent performance among all four nonhuman primate species. In Experiment 2, we tested adult humans in a similar procedure, and they outperformed the four nonhuman species but showed qualitatively similar performance. These results indicate that the ANS is conserved over the primate order.

Osteosarcoma tumor thrombus: a case report with a review of the literature.

Tumor thrombus arising from osteosarcoma is rare. We report the case of a 20-year-old man with proximal humerus osteosarcoma, accompanied by an extensive intravascular tumor thrombus extending into the heart. Our review of the literature found 14 previous reports on osteosarcoma with tumor thrombus. The combination of positron emission tomography and computed tomography is very useful in differentiating tumor thrombus from vascular thrombus, thereby avoiding unnecessary anticoagulation therapy. This same imaging combination can also be used to evaluate the response to treatment. Surgical resection of the tumor thrombus is highly recommended. The effect of tumor thrombus on survival is still unknown.

Prosimian primates show ratio dependence in spontaneous quantity discriminations.

We directly tested the predictions of the approximate number system (ANS) and the object file system in the spontaneous numerical judgments of prosimian primates. Prior work indicates that when human infants and a few species of non-human animals are given a single-trial choice between two sequentially baited buckets they choose the bucket with the greater amount of food but only when the quantities are small. This pattern of results has been interpreted as evidence that a limited capacity object file system is used to track small numbers of objects and that the ANS is not invoked under these circumstances. Here we tested prosimian primates in food choice comparisons that were chosen to contrast predictions of the ANS and object file systems. We found that prosimian primates consistently chose the larger of two sets when they differed by a 1:3 ratio regardless of whether both values were small (≤3), both values were large (>3), or there was one small and one large value. Prosimians were not able to robustly discriminate quantities that differed by a 1:2 ratio for the same three conditions, nor did they show a preference for small quantities that differed by a 2:3 ratio. These results implicate the ANS in the spontaneous numerical discriminations of non-human primates.

Context affects the numerical semantic congruity effect in rhesus monkeys (Macaca mulatta).

Do monkeys anchor their numerical judgments based on the context in which their choices are presented? We addressed this question by varying the numerical range across sessions while macaque monkeys made ordinal judgments. Monkeys were trained to make a conditional discrimination whereby they were reinforced for ordering arrays of dots in ascending or descending numerical order, dependent on a color cue. Monkeys were tested using two ranges of numerosities that converged on a single pair. Similar to the findings of Cantlon and Brannon (2005), we found a semantic congruity effect whereby decision time was systematically influenced by the congruity between the cue (ascending or descending) and the relative Numerical Magnitude of the stimuli within each range. Furthermore, monkeys showed a context effect, such that decision time for a given pair was dependent on whether it was a relatively small or large set of values compared to the other values presented in that session. This finding suggests that, similar to humans, the semantic congruity effect observed in monkeys is anchored by the context. Thus our data provide further evidence for the existence of a shared numerical comparison process in monkeys and humans.

A pilot study to assess attitudes, behaviors, and inter-office communication by psychiatrists and primary care providers in the care of older adults with schizophrenia.

INTRODUCTION: There is a lack of assessment tools and empirical data concerning clinician attitudes and behaviors with respect to the health care of older adults with schizophrenia. We develop a survey instrument of physician attitudes, behavior, and inter-office communication, and provide preliminary data on physician-related issues in the provision of health care to this population. METHODS: A semi-structured 20-item survey instrument was administered to a stratified convenience sample of 24 primary care physicians (PCPs) and 27 psychiatrists working in the New York metropolitan area. Using open ended and multiple choice items, scales, summed scores, and case vignettes, we assessed attitudes, experiences, and procedures in treating medical illnesses in older persons with schizophrenia. All scales had internal consistency reliabilities of >0.70. RESULTS: There were no differences between PCPs and psychiatrists in reported and anticipated behavior towards older adults with symptoms of schizophrenia, and both groups displayed favorable views. However, both groups had slightly negative stereotypes and attitudes concerning these patients. PCPs reported receiving information from psychiatrists slightly more than 0 to 10 percent of the time. CONCLUSIONS: Our preliminary findings indicated more favorable attitudes and behaviors by PCPs than had been anticipated based on earlier research with younger patients. The data suggest that the failure of older schizophrenia patients to receive adequate treatment may not be due primarily to clinicians' negative attitudes and behaviors, and that problems with communication may play a more important role.

Fast amplification of dynamic synaptic inputs in spinal motoneurons in vivo.

The ability of voltage-dependent inward currents (likely Na(+)) of the adult cat lumbar motoneurons to amplify rapidly changing (i.e., dynamic) synaptic inputs was investigated using in vivo intracellular recording techniques. Fast amplification was assessed by measuring the magnitude of the high-frequency (180 Hz) component of the Ia synaptic input due to tendon vibration as a function of somatic voltage and was compared with the previously observed amplification of steady inputs (steady state response of PICs to slow inputs). Data from 17 experiments show that amplification of the dynamic input indeed occurred and was directly linked to neuromodulatory drive (standard state: decerebrate with intact descending neuromodulatory systems vs. minimal state: pentobarbital with said systems significantly inhibited). Fast amplification factors averaged 2.0 +/- 0.7 (mean +/- SD) in the standard neuromodulatory state. That is, the effective synaptic current was nearly twice as large at its peak as it was at hyperpolarized levels, ranging as high as 2.6. Although fast amplification was often smaller than the amplification of steady inputs, the difference was not statistically significant. However, the voltage at which fast amplification began was approximately 10 mV more depolarized (P < 0.01). It is concluded that both dynamic and steady inputs can be amplified, but there may be differences in mechanism.