Continued safety and long-term effectiveness of onasemnogene abeparvovec in Ohio.

5q spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease caused by absence of the SMN1 gene with three FDA approved genetic therapies which significantly improve outcomes. The AAV9 mediated gene replacement therapy, onasemnogene abeparvovec, has the greatest potential for side effects. Here we report the safety and outcomes from 46 children treated with onasemnogene abeparvovec in the state of Ohio between December 2018 and January 2023. In our cohort, onasemnogene abeparvovec treatment remained safe and no child experienced any significant adverse events, including thrombotic microangiopathy, liver failure or death. All children experienced benefit, although the benefit in those with 2 copies of SMN2 was variable. 79 % of the children treated when symptomatic had a SMN2 modifying therapy added on. With careful screening and post treatment monitoring, onasemnogene abeparvovec is safe and effective for children with SMA in the state of Ohio, but more work needs to be done to ensure optimal outcomes for all children with 2 copies of SMN2.

The influence of regional wind patterns on air quality during forest fires near Sydney, Australia.

Particulate pollution from forest fire smoke threatens the health of communities by increasing the occurrence of respiratory illnesses. Wind drives both fire behaviour and smoke dispersal. Understanding regional wind patterns would assist in effectively managing smoke risk. Sydney, Australia is prone to smoke pollution because it has a large population close to fire-prone eucalypt forests. Here we use the self-organising maps (SOM) technique to identify sixteen unique wind classes for the Sydney region from days with active fires, including identifying sea breeze occurrence. We explored differences in PM2.5 levels between classes and between hazard reduction burning (HRB) and wildfire days. For HRB days, classes with the highest PM2.5 mostly had a sea breeze, whereas better air quality days usually had winds aligned across the region (e.g. all westerly). The wind class with the most HRB days had low wind speeds and a sea breeze and was among the worst wind classes for air quality. For wildfire days, days with a sea breeze were also generally of poor air quality but many classes had at least some poor air quality days, most of which were during the 2019-2020 east coast wildfires in New South Wales. Some poor air quality days occurred in wind classes that sent strong plumes directly over air quality stations, spread smoke over a wide area or transported smoke from outside the region. The classes identified may be useful in scheduling HRBs, for example, identifying days with low pollution risk to conduct an HRB, or for assisting in understanding pollution risk and sending health warnings during HRBs and wildfires. Further development of the approach may allow the creation of multi-day classifications for fire managers to plan HRB ignitions over several days to ensure better smoke dispersal. Further research could incorporate other weather predictors or focus on other regions.

Prediction of air quality in Sydney, Australia as a function of forest fire load and weather using Bayesian statistics.

Smoke from Hazard Reduction Burns (HRBs) and wildfires contains pollutants that are harmful to human health. This includes particulate matter less than 2.5 µm in diameter (PM2.5), which affects human cardiovascular and respiratory systems and can lead to increased hospitalisations and premature deaths. Better models are needed to predict PM2.5 levels associated with HRBs so that agencies can properly assess smoke pollution risk and balance smoke risk with the wildfire mitigation benefits of HRBs. Given this need, our aim was to develop a probabilistic model of daily PM2.5 using Bayesian regression. We focused on the region around Sydney, Australia, which regularly has hazard reduction burning, wildfires and associated smoke. We developed two regional models (mean daily and maximum daily) from observed PM2.5, weather reanalysis and satellite fire hotspot data. The models predict that the worst PM2.5 in Sydney occurs when PM2.5 was high the previous day, there is low ventilation index (i.e. the product of wind speed and planetary boundary layer height), low temperature, west to northwest winds in the Blue Mountains, an afternoon sea breeze and large areas of HRBs are being conducted, particularly to the west and north of Sydney. A major benefit of our approach is that models are fast to run, require simple inputs and Bayesian predictions convey both predicted PM2.5 and associated prediction uncertainty. Future research could include the application of similar methods to other regions, collecting more data to improve model precision and developing Bayesian PM2.5 models for wildfires.

A Late Paleocene age for Greenland's Hiawatha impact structure.

The ~31-km-wide Hiawatha structure, located beneath Hiawatha Glacier in northwestern Greenland, has been proposed as an impact structure that may have formed after the Pleistocene inception of the Greenland Ice Sheet. To date the structure, we conducted 40Ar/39Ar analyses on glaciofluvial sand and U-Pb analyses on zircon separated from glaciofluvial pebbles of impact melt rock, all sampled immediately downstream of Hiawatha Glacier. Unshocked zircon in the impact melt rocks dates to ~1915 million years (Ma), consistent with felsic intrusions found in local bedrock. The 40Ar/39Ar data indicate Late Paleocene resetting and shocked zircon dates to 57.99 ± 0.54 Ma, which we interpret as the impact age. Consequently, the Hiawatha impact structure far predates Pleistocene glaciation and is unrelated to either the Paleocene-Eocene Thermal Maximum or flood basalt volcanism in east Greenland. However, it was contemporaneous with the Paleocene Carbon Isotope Maximum, although the impact's exact paleoenvironmental and climatic significance awaits further investigation.

Potato Production in Northwestern Europe (Germany, France, the Netherlands, United Kingdom, Belgium): Characteristics, Issues, Challenges and Opportunities.

In Northwestern Europe, Germany, France, the Netherlands, the UK and Belgium constitute the biggest five potato producers, with total potato crop production around 60% of EU-28 production before Brexit. Soil and climate conditions are highly favourable for potato growth in this region. Production is under driving forces of (i) the potato processing industry, particularly in Belgium; (ii) the innovation for fresh potato in the UK, France and Germany; (iii) the leadership of Germany and the Netherlands for starch potato; and (iv) the dominance of the Netherlands for seed production. Based on an industrial agri-food production system, the region has the highest potato yield levels worldwide and developed relevant trade networks for export of seed, fresh and processed potato products in and outside Europe. Conventional and intensive potato production is widespread over the region, whilst organic production started to develop in Germany and France. Whether the coming decades will be as successful as the last ones for sustainable potato production will depend on how the sector and stakeholders of the whole potato value-chain will overcome new issues and challenges. These are mainly soil quality and health conservation, consequences of climate change, increasing bans on the use of plant protection products, tightening environmental standards, food waste reduction and increasing trade tensions hampering the flow of potatoes around the world. After a detailed description of the potato production in the region, this paper contains a SWOT analysis aiming to identify potential solutions to overcome environmental, technical, economic, political and societal issues in the region for sustainable potato production in the coming years and decades.

Experiments on the influence of spot fire and topography interaction on fire rate of spread.

Spotting is thought to increase wildfire rate of spread (ROS) and in some cases become the main mechanism for spread. The role of spotting in wildfire spread is controlled by many factors including fire intensity, number of and distance between spot fires, weather, fuel characteristics and topography. Through a set of 30 laboratory fire experiments on a 3 m x 4 m fuel bed, subject to air flow, we explored the influence of manually ignited spot fires (0, 1 or 2), the presence or absence of a model hill and their interaction on combined fire ROS (i.e. ROS incorporating main fire and merged spot fires). During experiments conducted on a flat fuel bed, spot fires (whether 1 or 2) had only a small influence on combined ROS. Slowest combined ROS was recorded when a hill was present and no spot fires were ignited, because the fires crept very slowly downslope and downwind of the hill. This was up to, depending on measurement interval, 5 times slower than ROS in the flat fuel bed experiments. However, ignition of 1 or 2 spot fires (with hill present) greatly increased combined ROS to similar levels as those recorded in the flat fuel bed experiments (depending on spread interval). The effect was strongest on the head fire, where spot fires merged directly with the main fire, but significant increases in off-centre ROS were also detected. Our findings suggest that under certain topographic conditions, spot fires can allow a fire to overcome the low spread potential of downslopes. Current models may underestimate wildfire ROS and fire arrival time in hilly terrain if the influence of spot fires on ROS is not incorporated into predictions.

Cabozantinib for relapsed neuroblastoma: Single institution case series.

Relapsed high-risk neuroblastoma has few effective therapies currently available or in development. Cabozantinib is an Food and Drug Administration approved multitargeted tyrosine kinase inhibitor for select adult malignancies with preclinical data suggesting efficacy against neuroblastoma. A safe and tolerable dose has been identified for children, but its efficacy remains unknown. We describe four children with relapsed metastatic neuroblastoma treated with cabozantinib. All four patients had extended disease control (two complete responsesfor >12 months, 2 stable disease >6 months) with manageable predictable toxicities requiring dose reduction in two patients. We discuss the potential for the use of cabozantinib in neuroblastoma.

Gene Replacement Therapy: A Primer for the Health-system Pharmacist.

PURPOSE: Comprehensive review of gene replacement therapy with guidance and expert opinion on handling and administration for pharmacists. SUMMARY: There are currently ∼2600 gene therapy clinical trials worldwide and 4 Food and Drug Administration (FDA)-approved gene therapy products available in the United States. Gene therapy and its handling are different from other drugs; however, there is a lack of guidance from the National Institutes of Health (NIH), FDA, Centers for Disease Control and Prevention (CDC), World Health Organization (WHO), and professional associations regarding their pharmaceutical application. Although the NIH stratifies the backbone biologicals of viral vectors in gene therapies into risk groups, incomplete information regarding minimization of exposure and reduction of risk exists. In the absence of defined guidance, individual institutions develop their own policies and procedures, which often differ and are often outdated. This review provides expert opinion on the role of pharmacists in institutional preparedness, as well as gene therapy handling and administration. A suggested infrastructural model for gene replacement therapy handling is described, including requisite equipment acquisition and standard operating procedure development. Personnel, patient, and caregiver education and training are discussed. CONCLUSION: Pharmacists have a key role in the proper handling and general management of gene replacement therapies, identifying risk level, establishing infrastructure, and developing adequate policies and protocols, particularly in the absence of consensus guidelines for the handling and transport of gene replacement therapies.

Last appearance of Homo erectus at Ngandong, Java, 117,000-108,000 years ago.

Homo erectus is the founding early hominin species of Island Southeast Asia, and reached Java (Indonesia) more than 1.5 million years ago1,2. Twelve H. erectus calvaria (skull caps) and two tibiae (lower leg bones) were discovered from a bone bed located about 20 m above the Solo River at Ngandong (Central Java) between 1931 and 19333,4, and are of the youngest, most-advanced form of H. erectus5-8. Despite the importance of the Ngandong fossils, the relationship between the fossils, terrace fill and ages have been heavily debated9-14. Here, to resolve the age of the Ngandong evidence, we use Bayesian modelling of 52 radiometric age estimates to establish-to our knowledge-the first robust chronology at regional, valley and local scales. We used uranium-series dating of speleothems to constrain regional landscape evolution; luminescence, 40argon/39argon (40Ar/39Ar) and uranium-series dating to constrain the sequence of terrace evolution; and applied uranium-series and uranium series-electron-spin resonance (US-ESR) dating to non-human fossils to directly date our re-excavation of Ngandong5,15. We show that at least by 500 thousand years ago (ka) the Solo River was diverted into the Kendeng Hills, and that it formed the Solo terrace sequence between 316 and 31 ka and the Ngandong terrace between about 140 and 92 ka. Non-human fossils recovered during the re-excavation of Ngandong date to between 109 and 106 ka (uranium-series minimum)16 and 134 and 118 ka (US-ESR), with modelled ages of 117 to 108 thousand years (kyr) for the H. erectus bone bed, which accumulated during flood conditions3,17. These results negate the extreme ages that have been proposed for the site and solidify Ngandong as the last known occurrence of this long-lived species.

Increasing optimal coagulation factor dosing in the paediatric emergency department: A quality improvement study.

INTRODUCTION: Haemophilia is a disorder complicated by bleeding episodes that require emergent medical evaluation. Factor replacement dosing can present challenges for emergency department (ED) care. AIMS: We aimed to reduce out-of-range factor dosing in the ED. Specifically, we sought to increase the number of haemophilia ED patient visits between encounters where sub-optimal factor dosing was administered from a baseline of 4-15 encounters. METHODS: A chart review was completed on all patients with haemophilia A (HA) or B (HB) seen in the ED for injuries requiring factor concentrate from September 2015 to August 2016. Injuries were classified as minor-requiring a 50% factor correction or major-requiring a 100% factor correction. Optimal dosing range was defined as 90%-120% of the institutional guideline goal for the degree of injury. The predicted optimal dose range for each patient was compared to the actual dose administered. RESULTS: Baseline data demonstrated optimal dosing range in 70% of encounters. There was no difference between patients with HA or HB in frequency of out-of-range dosing (P = 0.15). There was no difference in frequency of out-of-range dosing between types of clotting factor concentrate used. After initiation of quality improvement (QI) interventions, we achieved 16 encounters between out-of-range dosing, exceeding our goal of 15. However, this success was not sustained. CONCLUSION: Optimal coagulation factor dosing is important for patient care and resource management. QI interventions promoted increased accuracy of factor dosing for patients with haemophilia seen in the ED.

Evidence for extremely rapid magma ocean crystallization and crust formation on Mars.

The formation of a primordial crust is a critical step in the evolution of terrestrial planets but the timing of this process is poorly understood. The mineral zircon is a powerful tool for constraining crust formation because it can be accurately dated with the uranium-to-lead (U-Pb) isotopic decay system and is resistant to subsequent alteration. Moreover, given the high concentration of hafnium in zircon, the lutetium-to-hafnium (176Lu-176Hf) isotopic decay system can be used to determine the nature and formation timescale of its source reservoir1-3. Ancient igneous zircons with crystallization ages of around 4,430 million years (Myr) have been reported in Martian meteorites that are believed to represent regolith breccias from the southern highlands of Mars4,5. These zircons are present in evolved lithologies interpreted to reflect re-melted primary Martian crust 4 , thereby potentially providing insight into early crustal evolution on Mars. Here, we report concomitant high-precision U-Pb ages and Hf-isotope compositions of ancient zircons from the NWA 7034 Martian regolith breccia. Seven zircons with mostly concordant U-Pb ages define 207Pb/206Pb dates ranging from 4,476.3 ± 0.9 Myr ago to 4,429.7 ± 1.0 Myr ago, including the oldest directly dated material from Mars. All zircons record unradiogenic initial Hf-isotope compositions inherited from an enriched, andesitic-like crust extracted from a primitive mantle no later than 4,547 Myr ago. Thus, a primordial crust existed on Mars by this time and survived for around 100 Myr before it was reworked, possibly by impacts4,5, to produce magmas from which the zircons crystallized. Given that formation of a stable primordial crust is the end product of planetary differentiation, our data require that the accretion, core formation and magma ocean crystallization on Mars were completed less than 20 Myr after the formation of the Solar System. These timescales support models that suggest extremely rapid magma ocean crystallization leading to a gravitationally unstable stratified mantle, which subsequently overturns, resulting in decompression melting of rising cumulates and production of a primordial basaltic to andesitic crust6,7.

Age and context of the oldest known hominin fossils from Flores.

Recent excavations at the early Middle Pleistocene site of Mata Menge in the So'a Basin of central Flores, Indonesia, have yielded hominin fossils attributed to a population ancestral to Late Pleistocene Homo floresiensis. Here we describe the age and context of the Mata Menge hominin specimens and associated archaeological findings. The fluvial sandstone layer from which the in situ fossils were excavated in 2014 was deposited in a small valley stream around 700 thousand years ago, as indicated by (40)Ar/(39)Ar and fission track dates on stratigraphically bracketing volcanic ash and pyroclastic density current deposits, in combination with coupled uranium-series and electron spin resonance dating of fossil teeth. Palaeoenvironmental data indicate a relatively dry climate in the So'a Basin during the early Middle Pleistocene, while various lines of evidence suggest the hominins inhabited a savannah-like open grassland habitat with a wetland component. The hominin fossils occur alongside the remains of an insular fauna and a simple stone technology that is markedly similar to that associated with Late Pleistocene H. floresiensis.

Revised stratigraphy and chronology for Homo floresiensis at Liang Bua in Indonesia.

Homo floresiensis, a primitive hominin species discovered in Late Pleistocene sediments at Liang Bua (Flores, Indonesia), has generated wide interest and scientific debate. A major reason this taxon is controversial is because the H. floresiensis-bearing deposits, which include associated stone artefacts and remains of other extinct endemic fauna, were dated to between about 95 and 12 thousand calendar years (kyr) ago. These ages suggested that H. floresiensis survived until long after modern humans reached Australia by ~50 kyr ago. Here we report new stratigraphic and chronological evidence from Liang Bua that does not support the ages inferred previously for the H. floresiensis holotype (LB1), ~18 thousand calibrated radiocarbon years before present (kyr cal. BP), or the time of last appearance of this species (about 17 or 13-11 kyr cal. BP). Instead, the skeletal remains of H. floresiensis and the deposits containing them are dated to between about 100 and 60 kyr ago, whereas stone artefacts attributable to this species range from about 190 to 50 kyr in age. Whether H. floresiensis survived after 50 kyr ago--potentially encountering modern humans on Flores or other hominins dispersing through southeast Asia, such as Denisovans--is an open question.

Earliest hominin occupation of Sulawesi, Indonesia.

Sulawesi is the largest and oldest island within Wallacea, a vast zone of oceanic islands separating continental Asia from the Pleistocene landmass of Australia and Papua (Sahul). By one million years ago an unknown hominin lineage had colonized Flores immediately to the south, and by about 50 thousand years ago, modern humans (Homo sapiens) had crossed to Sahul. On the basis of position, oceanic currents and biogeographical context, Sulawesi probably played a pivotal part in these dispersals. Uranium-series dating of speleothem deposits associated with rock art in the limestone karst region of Maros in southwest Sulawesi has revealed that humans were living on the island at least 40 thousand years ago (ref. 5). Here we report new excavations at Talepu in the Walanae Basin northeast of Maros, where in situ stone artefacts associated with fossil remains of megafauna (Bubalus sp., Stegodon and Celebochoerus) have been recovered from stratified deposits that accumulated from before 200 thousand years ago until about 100 thousand years ago. Our findings suggest that Sulawesi, like Flores, was host to a long-established population of archaic hominins, the ancestral origins and taxonomic status of which remain elusive.

Evaluation of Parenteral Nutrition Errors in an Era of Drug Shortages.

BACKGROUND: Ingredient shortages have forced many organizations to change practices or use unfamiliar ingredients, which creates potential for error. Parenteral nutrition (PN) has been significantly affected, as every ingredient in PN has been impacted in recent years. MATERIALS AND METHODS: Ingredient errors involving PN that were reported to the national anonymous MedMARx database between May 2009 and April 2011 were reviewed. Errors were categorized by ingredient, node, and severity. Categorization was validated by experts in medication safety and PN. A timeline of PN ingredient shortages was developed and compared with the PN errors to determine if events correlated with an ingredient shortage. This information was used to determine the prevalence and change in harmful PN errors during periods of shortage, elucidating whether a statistically significant difference exists in errors during shortage as compared with a control period (ie, no shortage). RESULTS: There were 1311 errors identified. Nineteen errors were associated with harm. Fat emulsions and electrolytes were the PN ingredients most frequently associated with error. Insulin was the ingredient most often associated with patient harm. On individual error review, PN shortages were described in 13 errors, most of which were associated with intravenous fat emulsions; none were associated with harm. There was no correlation of drug shortages with the frequency of PN errors. CONCLUSION: Despite the significant impact that shortages have had on the PN use system, no adverse impact on patient safety could be identified from these reported PN errors.

Astronomically calibrated 40Ar/39Ar age for the Toba supereruption and global synchronization of late Quaternary records.

The Toba supereruption in Sumatra, ∼74 thousand years (ka) ago, was the largest terrestrial volcanic event of the Quaternary. Ash and sulfate aerosols were deposited in both hemispheres, forming a time-marker horizon that can be used to synchronize late Quaternary records globally. A precise numerical age for this event has proved elusive, with dating uncertainties larger than the millennial-scale climate cycles that characterized this period. We report an astronomically calibrated (40)Ar/(39)Ar age of 73.88 ± 0.32 ka (1σ, full external errors) for sanidine crystals extracted from Toba deposits in the Lenggong Valley, Malaysia, 350 km from the eruption source and 6 km from an archaeological site with stone artifacts buried by ash. If these artifacts were made by Homo sapiens, as has been suggested, then our age indicates that modern humans had reached Southeast Asia by ∼74 ka ago. Our (40)Ar/(39)Ar age is an order-of-magnitude more precise than previous estimates, resolving the timing of the eruption to the middle of the cold interval between Dansgaard-Oeschger events 20 and 19, when a peak in sulfate concentration occurred as registered by Greenland ice cores. This peak is followed by a ∼10 °C drop in the Greenland surface temperature over ∼150 y, revealing the possible climatic impact of the eruption. Our (40)Ar/(39)Ar age also provides a high-precision calibration point for other ice, marine, and terrestrial archives containing Toba sulfates and ash, facilitating their global synchronization at unprecedented resolution for a critical period in Earth and human history beyond the range of (14)C dating.

Advances in on-line drinking water quality monitoring and early warning systems.

Significant advances have been made in recent years in technologies to monitor drinking water quality for source water protection, treatment operations, and distribution system management, in the event of accidental (or deliberate) contamination. Reports prepared through the Global Water Research Coalition (GWRC) and United States Environment Protection Agency (USEPA) agree that while many emerging technologies show promise, they are still some years from being deployed on a large scale. Further underpinning their viability is a need to interpret data in real time and implement a management strategy in response. This review presents the findings of an international study into the state of the art in this field. These results are based on visits to leading water utilities, research organisations and technology providers throughout Europe, the United States and Singapore involved in the development and deployment of on-line monitoring technology for the detection of contaminants in water.

Hominins on Flores, Indonesia, by one million years ago.

Previous excavations at Mata Menge and Boa Lesa in the Soa Basin of Flores, Indonesia, recovered stone artefacts in association with fossilized remains of the large-bodied Stegodon florensis florensis. Zircon fission-track ages from these sites indicated that hominins had colonized the island by 0.88 +/- 0.07 million years (Myr) ago. Here we describe the contents, context and age of Wolo Sege, a recently discovered archaeological site in the Soa Basin that has in situ stone artefacts and that lies stratigraphically below Mata Menge and immediately above the basement breccias of the basin. We show using (40)Ar/(39)Ar dating that an ignimbrite overlying the artefact layers at Wolo Sege was erupted 1.02 +/- 0.02 Myr ago, providing a new minimum age for hominins on Flores. This predates the disappearance from the Soa Basin of 'pygmy' Stegodon sondaari and Geochelone spp. (giant tortoise), as evident at the nearby site of Tangi Talo, which has been dated to 0.90 +/- 0.07 Myr ago. It now seems that this extirpation or possible extinction event and the associated faunal turnover were the result of natural processes rather than the arrival of hominins. It also appears that the volcanic and fluvio-lacustrine deposits infilling the Soa Basin may not be old enough to register the initial arrival of hominins on the island.