Early Australian experience in the maintenance of schizophrenia management with 3-monthly paliperidone palmitate

Objectives: Real-world experience from a 6-month product familiarization programme (PFP) for 3-monthly paliperidone palmitate in schizophrenia maintenance treatment. Methods: Prescribers completed an online questionnaire for each patient at enrolment with further questions at second dose (re-supply) stage and a second survey of their overall experience at the end. Results: Ninety-four patients were enrolled and received a first dose and 23 received a second dose within the 6-month programme; 51.1% had been hospitalised for symptom relapse in the previous 2 years. Reasons for prescribing were convenience of 3-monthly dosing for patients (94.7%) and patient choice (54.6%). Prescribers followed-up at least once-monthly (69.6% cases) and indicated in 48.9% they would consider shared GP care. All patients were satisfied with symptom control and either maintained functioning or showed improvement. Clinicians felt confident with administration and identifying suitable patients and were all \u27satisfied\u27 or \u27somewhat satisfied\u27 with efficacy and tolerability. All felt patients\u27 treatment goals were either \u27met\u27 (81.3%) or \u27partly met\u27 (18.7%) and none reported dissatisfaction with relapse prevention. Conclusions: Convenient 3-monthly dosing was preferred by clinicians and patients, and symptoms were adequately managed. This has the potential to improve adherence and lead to better outcomes as patients only need four intramuscular doses per year

Elevated Mechanical Loading When Young Provides Lifelong Benefits to Cortical Bone Properties in Female Rats Independent of a Surgically Induced Menopause

Exercise that mechanically loads the skeleton is advocated when young to enhance lifelong bone health. Whether the skeletal benefits of elevated loading when young persist into adulthood and after menopause are important questions. This study investigated the influence of a surgically induced menopause in female Sprague-Dawley rats on the lifelong maintenance of the cortical bone benefits of skeletal loading when young. Animals had their right forearm extrinsically loaded 3 d/wk between 4 and 10 weeks of age using the forearm axial compression loading model. Left forearms were internal controls and not loaded. Animals were subsequently detrained (restricted to cage activities) for 94 weeks (until age 2 years), with ovariectomy (OVX) or sham-OVX surgery being performed at 24 weeks of age. Loading enhanced midshaft ulna cortical bone mass, structure, and estimated strength. These benefits persisted lifelong and contributed to loaded ulnas having greater strength after detraining. Loading also had effects on cortical bone quality. The benefits of loading when young were not influenced by a surgically induced menopause because there were no interactions between loading and surgery. However, OVX had independent effects on cortical bone mass, structure, and estimated strength at early postsurgery time points (up to age 58 weeks) and bone quality measures. These data indicate skeletal loading when young had lifelong benefits on cortical bone properties that persisted independent of a surgically induced menopause. This suggests that skeletal loading associated with exercise when young may provide lifelong antifracture benefits by priming the skeleton to offset the cortical bone changes associated with aging and menopause

A mission concept for the low-cost large-scale exploration and characterisation of near earth objects

This paper presents the preliminary mission and science analysis of a new mission concept for the large scale, low-cost exploration of Near Earth Objects (NEOs). The concept is to enable close range observations of NEOs by performing close flybys of a series of NEOs at one of their nodal points, with pairs of small spacecraft flying in formation. The paper presents a preliminary assessment of accessible asteroids and multi-target tour trajectories from data available in the JPL small-body database. The main instruments on board each spacecraft are a camera and a LIDAR which together can be used for orbit determination, sur-face imaging, direct asteroid ranging and asteroid mass estimation via intersatellite ranging. The paper provides a qualitative and quantitative assessment of the measurable quantities during each flyby. In particular, the feasibility of a novel method of NEO mass estimation is assessed

Cortical and trabecular bone benefits of mechanical loading are maintained long term in mice independent of ovariectomy.

Skeletal loading enhances cortical and trabecular bone properties. How long these benefits last after loading cessation remains an unresolved, clinically relevant question. This study investigated long-term maintenance of loading-induced cortical and trabecular bone benefits in female C57BL/6 mice and the influence of a surgically induced menopause on the maintenance. Sixteen-week-old animals had their right tibia extrinsically loaded 3 days/week for 4 weeks using the mouse tibial axial compression loading model. Left tibias were not loaded and served as internal controls. Animals were subsequently detrained (restricted to cage activities) for 0, 4, 8, 26, or 52 weeks, with ovariectomy (OVX) or sham-OVX surgery being performed at 0 weeks detraining. Loading increased midshaft tibia cortical bone mass, size, and strength, and proximal tibia bone volume fraction. The cortical bone mass, area, and thickness benefits of loading were lost by 26 weeks of detraining because of heightened medullary expansion. However, loading-induced benefits on bone total area and strength were maintained at each detraining time point. Similarly, the benefits of loading on bone volume fraction persisted at all detraining time points. The long-term benefits of loading on both cortical and trabecular bone were not influenced by a surgically induced menopause because there were no interactions between loading and surgery. However, OVX had independent effects on cortical bone properties at early (4 and 8 weeks) detraining time points and trabecular bone properties at all detraining time points. These cumulative data indicate loading has long-term benefits on cortical bone size and strength (but not mass) and trabecular bone morphology, which are not influenced by a surgically induced menopause. This suggests skeletal loading associated with physical activity may provide long-term benefits by preparing the skeleton to offset both the cortical and trabecular bone changes associated with aging and menopause

Datasheets for Machine Learning Sensors

Machine learning (ML) sensors offer a new paradigm for sensing that enables intelligence at the edge while empowering end-users with greater control of their data. As these ML sensors play a crucial role in the development of intelligent devices, clear documentation of their specifications, functionalities, and limitations is pivotal. This paper introduces a standard datasheet template for ML sensors and discusses its essential components including: the system's hardware, ML model and dataset attributes, end-to-end performance metrics, and environmental impact. We provide an example datasheet for our own ML sensor and discuss each section in detail. We highlight how these datasheets can facilitate better understanding and utilization of sensor data in ML applications, and we provide objective measures upon which system performance can be evaluated and compared. Together, ML sensors and their datasheets provide greater privacy, security, transparency, explainability, auditability, and user-friendliness for ML-enabled embedded systems. We conclude by emphasizing the need for standardization of datasheets across the broader ML community to ensure the responsible and effective use of sensor data

The Redox Cofactor F-420 Protects Mycobacteria from Diverse Antimicrobial Compounds and Mediates a Reductive Detoxification System

A defining feature of mycobacterial redox metabolism is the use of an unusual deazaflavin cofactor, F420. This cofactor enhances the persistence of environmental and pathogenic mycobacteria, including after antimicrobial treatment, although the molecular basis for this remains to be understood. In this work, we explored our hypothesis that F420 enhances persistence by serving as a cofactor in antimicrobial-detoxifying enzymes. To test this, we performed a series of phenotypic, biochemical, and analytical chemistry studies in relation to the model soil bacterium Mycobacterium smegmatis. Mutant strains unable to synthesize or reduce F420 were found to be more susceptible to a wide range of antibiotic and xenobiotic compounds. Compounds from three classes of antimicrobial compounds traditionally resisted by mycobacteria inhibited the growth of F420 mutant strains at subnanomolar concentrations, namely, furanocoumarins (e.g., methoxsalen), arylmethanes (e.g., malachite green), and quinone analogues (e.g., menadione). We demonstrated that promiscuous F420H2-dependent reductases directly reduce these compounds by a mechanism consistent with hydride transfer. Moreover, M. smegmatis strains unable to make F420H2 lost the capacity to reduce and detoxify representatives of the furanocoumarin and arylmethane compound classes in whole-cell assays. In contrast, mutant strains were only slightly more susceptible to clinical antimycobacterials, and this appeared to be due to indirect effects of F420 loss of function (e.g., redox imbalance) rather than loss of a detoxification system. Together, these data show that F420 enhances antimicrobial resistance in mycobacteria and suggest that one function of the F420H2-dependent reductases is to broaden the range of natural products that mycobacteria and possibly other environmental actinobacteria can reductively detoxify

Widening Access to Applied Machine Learning with TinyML

Broadening access to both computational and educational resources is critical to diffusing machine-learning (ML) innovation. However, today, most ML resources and experts are siloed in a few countries and organizations. In this paper, we describe our pedagogical approach to increasing access to applied ML through a massive open online course (MOOC) on Tiny Machine Learning (TinyML). We suggest that TinyML, ML on resource-constrained embedded devices, is an attractive means to widen access because TinyML both leverages low-cost and globally accessible hardware, and encourages the development of complete, self-contained applications, from data collection to deployment. To this end, a collaboration between academia (Harvard University) and industry (Google) produced a four-part MOOC that provides application-oriented instruction on how to develop solutions using TinyML. The series is openly available on the edX MOOC platform, has no prerequisites beyond basic programming, and is designed for learners from a global variety of backgrounds. It introduces pupils to real-world applications, ML algorithms, data-set engineering, and the ethical considerations of these technologies via hands-on programming and deployment of TinyML applications in both the cloud and their own microcontrollers. To facilitate continued learning, community building, and collaboration beyond the courses, we launched a standalone website, a forum, a chat, and an optional course-project competition. We also released the course materials publicly, hoping they will inspire the next generation of ML practitioners and educators and further broaden access to cutting-edge ML technologies.Comment: Understanding the underpinnings of the TinyML edX course series: https://www.edx.org/professional-certificate/harvardx-tiny-machine-learnin

Cofactor tail length modulates catalysis of bacterial F420-dependent oxidoreductases

F420 is a microbial cofactor that mediates a wide range of physiologically important and industrially relevant redox reactions, including in methanogenesis and tetracycline biosynthesis. This deazaflavin comprises a redox-active isoalloxazine headgroup conjugated to a lactyloligoglutamyl tail. Here we studied the catalytic significance of the oligoglutamate chain, which differs in length between bacteria and archaea. We purified short-chain F420 (two glutamates) from a methanogen isolate and long-chain F420 (five to eight glutamates) from a recombinant mycobacterium, confirming their different chain lengths by HPLC and LC/MS analysis. F420 purified from both sources was catalytically compatible with purified enzymes from the three major bacterial families of F420-dependent oxidoreductases. However, long-chain F420 bound to these enzymes with a six- to ten-fold higher affinity than short-chain F420. The cofactor side chain also significantly modulated the kinetics of the enzymes, with long-chain F420 increasing the substrate affinity (lower Km) but reducing the turnover rate (lower kcat) of the enzymes. Molecular dynamics simulations and comparative structural analysis suggest that the oligoglutamate chain of F420 makes dynamic electrostatic interactions with conserved surface residues of the oxidoreductases while the headgroup binds the catalytic site. In conjunction with the kinetic data, this suggests that electrostatic interactions made by the oligoglutamate tail result in higher-affinity, lower-turnover catalysis. Physiologically, we propose that bacteria have selected for long-chain F420 to better control cellular redox reactions despite tradeoffs in catalytic rate. Conversely, this suggests that industrial use of shorter-length F420 will greatly increase the rates of bioremediation and biocatalysis processes relying on purified F420-dependent oxidoreductasesThis work was supported by a CSIRO Office of the Chief Executive Postdoctoral Fellowship and an ARC DECRA Fellowship (DE170100310) awarded to CG, a Marsden Grant (GNS-035) awarded to CC, and Australian Research Council grants (DE120102673, DP130102144) awarded to CJ

Inhibition of CaMKK2 Enhances Fracture Healing by Stimulating Indian Hedgehog Signaling and Accelerating Endochondral Ossification

Approximately 10% of all bone fractures do not heal, resulting in patient morbidity and healthcare costs. However, no pharmacological treatments are currently available to promote efficient bone healing. Inhibition of Ca2+/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) reverses age-associated loss of trabecular and cortical bone volume and strength in mice. In the current study, we investigated the role of CaMKK2 in bone fracture healing and show that its pharmacological inhibition using STO-609 accelerates early cellular and molecular events associated with endochondral ossification, resulting in a more rapid and efficient healing of the fracture. Within 7 days postfracture, treatment with STO-609 resulted in enhanced Indian hedgehog signaling, paired-related homeobox (PRX1)-positive mesenchymal stem cell (MSC) recruitment, and chondrocyte differentiation and hypertrophy, along with elevated expression of osterix, vascular endothelial growth factor, and type 1 collagen at the fracture callus. Early deposition of primary bone by osteoblasts resulted in STO-609–treated mice possessing significantly higher callus bone volume by 14 days following fracture. Subsequent rapid maturation of the bone matrix bestowed fractured bones in STO-609–treated animals with significantly higher torsional strength and stiffness by 28 days postinjury, indicating accelerated healing of the fracture. Previous studies indicate that fixed and closed femoral fractures in the mice take 35 days to fully heal without treatment. Therefore, our data suggest that STO-609 potentiates a 20% acceleration of the bone healing process. Moreover, inhibiting CaMKK2 also imparted higher mechanical strength and stiffness at the contralateral cortical bone within 4 weeks of treatment. Taken together, the data presented here underscore the therapeutic potential of targeting CaMKK2 to promote efficacious and rapid healing of bone fractures and as a mechanism to strengthen normal bones