Challenges in control of COVID-19: short doubling time and long delay to effect of interventions

Early assessments of the growth rate of COVID-19 were subject to significant uncertainty, as expected with limited data and difficulties in case ascertainment, but as cases were recorded in multiple countries, more robust inferences could be made. Using multiple countries, data streams and methods, we estimated that, when unconstrained, European COVID-19 confirmed cases doubled on average every 3 days (range 2.2-4.3 days) and Italian hospital and intensive care unit admissions every 2-3 days; values that are significantly lower than the 5-7 days dominating the early published literature. Furthermore, we showed that the impact of physical distancing interventions was typically not seen until at least 9 days after implementation, during which time confirmed cases could grow eightfold. We argue that such temporal patterns are more critical than precise estimates of the time-insensitive basic reproduction number R0 for initiating interventions, and that the combination of fast growth and long detection delays explains the struggle in countries' outbreak response better than large values of R0 alone. One year on from first reporting these results, reproduction numbers continue to dominate the media and public discourse, but robust estimates of unconstrained growth remain essential for planning worst-case scenarios, and detection delays are still key in informing the relaxation and re-implementation of interventions. This article is part of the theme issue 'Modelling that shaped the early COVID-19 pandemic response in the UK'

Hydroclimatic Variability and Predictability: A Survey of Recent Research

Recent research in large-scale hydroclimatic variability is surveyed, focusing on five topics: (i) variability in general, (ii) droughts, (iii) floods, (iv) land-atmosphere coupling, and (v) hydroclimatic prediction. Each surveyed topic is supplemented by illustrative examples of recent research, as presented at a 2016 symposium honoring the career of Professor Eric Wood. Taken together, the recent literature and the illustrative examples clearly show that current research into hydroclimatic variability is strong, vibrant, and multifaceted

Variability in transport of terrigenous material on the shelves and the deep Arctic Ocean during the Holocene

Arctic coastal zones serve as a sensitive filter for terrigenous matter input onto the shelves via river discharge and coastal erosion. This material is further distributed across the Arctic by ocean currents and sea ice. The coastal regions are particularly vulnerable to changes related to recent climate change. We compiled a pan-Arctic review that looks into the changing Holocene sources, transport processes and sinks of terrigenous sediment in the Arctic Ocean. Existing palaeoceanographic studies demonstrate how climate warming and the disappearance of ice sheets during the early Holocene initiated eustatic sea-level rise that greatly modified the physiography of the Arctic Ocean. Sedimentation rates over the shelves and slopes were much greater during periods of rapid sea-level rise in the early and middle Holocene, as a result of the relative distance to the terrestrial sediment sources. However, estimates of suspended sediment delivery through major Arctic rivers do not indicate enhanced delivery during this time, which suggests enhanced rates of coastal erosion. The increased supply of terrigenous material to the outer shelves and deep Arctic Ocean in the early and middle Holocene might serve as analogous to forecast changes in the future Arctic.Peer reviewe

Variability in transport of terrigenous material on the shelves and the deep Arctic Ocean during the Holocene

Arctic coastal zones serve as a sensitive filter for terrigenous matter input onto the shelves via river discharge and coastal erosion. This material is further distributed across the Arctic by ocean currents and sea ice. The coastal regions are particularly vulnerable to changes related to recent climate change. We compiled a pan-Arctic review that looks into the changing Holocene sources, transport processes and sinks of terrigenous sediment in the Arctic Ocean. Existing palaeoceanographic studies demonstrate how climate warming and the disappearance of ice sheets during the early Holocene initiated eustatic sea-level rise that greatly modified the physiography of the Arctic Ocean. Sedimentation rates over the shelves and slopes were much greater during periods of rapid sea-level rise in the early and middle Holocene, as a result of the relative distance to the terrestrial sediment sources. However, estimates of suspended sediment delivery through major Arctic rivers do not indicate enhanced delivery during this time, which suggests enhanced rates of coastal erosion. The increased supply of terrigenous material to the outer shelves and deep Arctic Ocean in the early and middle Holocene might serve as analogous to forecast changes in the future Arctic.Peer reviewe

Challenges in control of COVID-19: short doubling time and long delay to effect of interventions

From The Royal Society via Jisc Publications RouterHistory: accepted 2021-04-21, pub-electronic 2021-05-31, pub-print 2021-07-19Article version: VoRPublication status: PublishedFunder: Wellcome Trust; Id: http://dx.doi.org/10.13039/100004440; Grant(s): 107652/Z/15/Z, 202562/Z/16/ZFunder: Institute of Population and Public Health; Id: http://dx.doi.org/10.13039/501100000036; Grant(s): CIHR 2019 Novel Coronavirus (COVID-19) rapid reseaFunder: National Institute for Health Research; Id: http://dx.doi.org/10.13039/501100000272Funder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100000265; Grant(s): MR/S020462/1, MR/V038613/1Funder: Public Health Research Programme; Id: http://dx.doi.org/10.13039/501100001921Funder: Biotechnology and Biological Sciences Research Council; Id: http://dx.doi.org/10.13039/501100000268; Grant(s): BB/R009236/1Funder: Royal Society; Id: http://dx.doi.org/10.13039/501100000288; Grant(s): INF\R2\180067Funder: Alan Turing Institute; Id: http://dx.doi.org/10.13039/100012338Early assessments of the growth rate of COVID-19 were subject to significant uncertainty, as expected with limited data and difficulties in case ascertainment, but as cases were recorded in multiple countries, more robust inferences could be made. Using multiple countries, data streams and methods, we estimated that, when unconstrained, European COVID-19 confirmed cases doubled on average every 3 days (range 2.2–4.3 days) and Italian hospital and intensive care unit admissions every 2–3 days; values that are significantly lower than the 5–7 days dominating the early published literature. Furthermore, we showed that the impact of physical distancing interventions was typically not seen until at least 9 days after implementation, during which time confirmed cases could grow eightfold. We argue that such temporal patterns are more critical than precise estimates of the time-insensitive basic reproduction number R0 for initiating interventions, and that the combination of fast growth and long detection delays explains the struggle in countries' outbreak response better than large values of R0 alone. One year on from first reporting these results, reproduction numbers continue to dominate the media and public discourse, but robust estimates of unconstrained growth remain essential for planning worst-case scenarios, and detection delays are still key in informing the relaxation and re-implementation of interventions. This article is part of the theme issue ‘Modelling that shaped the early COVID-19 pandemic response in the UK’

Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial

Tau plays a key role in Alzheimer’s disease (AD) pathophysiology, and accumulating evidence suggests that lowering tau may reduce this pathology. We sought to inhibit MAPT expression with a tau-targeting antisense oligonucleotide (MAPTRx) and reduce tau levels in patients with mild AD. A randomized, double-blind, placebo-controlled, multiple-ascending dose phase 1b trial evaluated the safety, pharmacokinetics and target engagement of MAPTRx. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal bolus administrations of MAPTRx or placebo every 4 or 12 weeks during the 13-week treatment period, followed by a 23 week post-treatment period. The primary endpoint was safety. The secondary endpoint was MAPTRx pharmacokinetics in cerebrospinal fluid (CSF). The prespecified key exploratory outcome was CSF total-tau protein concentration. Forty-six patients enrolled in the trial, of whom 34 were randomized to MAPTRx and 12 to placebo. Adverse events were reported in 94% of MAPTRx-treated patients and 75% of placebo-treated patients; all were mild or moderate. No serious adverse events were reported in MAPTRx-treated patients. Dose-dependent reduction in the CSF total-tau concentration was observed with greater than 50% mean reduction from baseline at 24 weeks post-last dose in the 60 mg (four doses) and 115 mg (two doses) MAPTRx groups. Clinicaltrials.gov registration number: NCT03186989

Introductory programming: a systematic literature review

As computing becomes a mainstream discipline embedded in the school curriculum and acts as an enabler for an increasing range of academic disciplines in higher education, the literature on introductory programming is growing. Although there have been several reviews that focus on specific aspects of introductory programming, there has been no broad overview of the literature exploring recent trends across the breadth of introductory programming. This paper is the report of an ITiCSE working group that conducted a systematic review in order to gain an overview of the introductory programming literature. Partitioning the literature into papers addressing the student, teaching, the curriculum, and assessment, we explore trends, highlight advances in knowledge over the past 15 years, and indicate possible directions for future research

Dominant-negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome.

SLC1A4 is a trimeric neutral amino acid transporter essential for shuttling L-serine from astrocytes into neurons. Individuals with biallelic variants in SLC1A4 are known to have spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) syndrome, but individuals with heterozygous variants are not thought to have disease. We identify an 8-year-old patient with global developmental delay, spasticity, epilepsy, and microcephaly who has a de novo heterozygous three amino acid duplication in SLC1A4 (L86_M88dup). We demonstrate that L86_M88dup causes a dominant-negative N-glycosylation defect of SLC1A4, which in turn reduces the plasma membrane localization of SLC1A4 and the transport rate of SLC1A4 for L-serine