Publications

A closed-loop control system drives progression of the coupled stalked and swarmer cell cycles of the bacterium Caulobacter crescentus in a near-mechanical step-like fashion. The cell-cycle control has a cyclical genetic circuit composed of four regulatory proteins with tight coupling to processive chromosome replication and cell division subsystems. We report a hybrid simulation of the coupled cell-cycle control system, including asymmetric cell division and responses to external starvation signals, that replicates mRNA and protein concentration patterns and is consistent with observed mutant phenotypes. An asynchronous sequential digital circuit model equivalent to the validated simulation model was created. Formal model-checking analysis of the digital circuit showed that the cell-cycle control is robust to intrinsic stochastic variations in reaction rates and nutrient supply, and that it reliably stops and restarts to accommodate nutrient starvation. Model checking also showed that mechanisms involving methylation-state changes in regulatory promoter regions during DNA replication increase the robustness of the cell-cycle control. The hybrid cell-cycle simulation implementation is inherently extensible and provides a promising approach for development of whole-cell behavioral models that can replicate the observed functionality of the cell and its responses to changing environmental conditions.

The number of foci reported in small VBM studies and even in meta-analyses with few studies may often be inflated. This picture is consistent with reporting biases affecting small studies.

On-chip inductance is becoming increasingly important as technology continues to scale. This paper describes a way to characterize inductive effects in interconnects. It uses realistic test structures that study the effect of mutual couplings to local interconnects, to random lines connected to on-chip drivers, and to typical power and ground grids. The use of S parameters to characterize the inductance allows a large number of lines to be extracted while requiring only a small overhead measurement of dummy open pads to remove measurement parasitics. It also enables direct extraction of the frequency-dependent R, L, G, C parameters. The results are summarized with curve-fitted formulas of inductance and resistance over a wide range of line spacings and line widths. The significance of the frequency dependence is illustrated with transient analysis of a typical repeater circuit in a 0.25-/spl mu/m technology. A model that captures the frequency dependency of the extracted parameters accurately predicts the performance of a new inductance-sensitive ring oscillator.

ABSTRACT Importance There is concern that post-acute SARS-CoV-2 infection health outcomes (“post-COVID syndrome”) in children could be a serious problem but at the same time there is concern about the validity of reported associations between infection and long-term outcomes. Objective To systematically assess the validity of reported post-acute SARS-CoV-2 infection health outcomes in children. Evidence Review A search on PubMed and Web of Science was conducted to identify studies published up to January 22, 2022, that reported on post-acute SARS-CoV-2 infection health outcomes in children (<18 years) with follow-up of ≥2 months since detection of infection or ≥1 month since recovery from acute illness. We assessed the consideration of confounding bias and causality, and the risk of bias. Findings 21 studies including 81,896 children reported up to 97 symptoms with follow-up periods of 2-11.5 months. Fifteen studies had no control group. The reported proportion of children with post-COVID syndrome was between 0% and 66.5% in children with SARS-CoV-2 infection (n=16,986) and 2% to 53.3% in children without SARS-CoV-2 infection (n=64,910). Only 2 studies made a clear causal interpretation of an association of SARS-CoV-2 infection and the main outcome of “post-COVID syndrome” and provided recommendations regarding prevention measures. Two studies mentioned potential limitations in the conclusion of the main text but none of the 21 studies mentioned any limitations in the abstract nor made a clear statement for cautious interpretation. The validity of all 21 studies was seriously limited due to an overall critical risk of bias (critical risk for confounding bias [n=21]; serious or critical risk for selection bias [n=19]; serious risk for misclassification bias [n=3], for bias due to missing data [n=14] and for outcome measurement [n=12]; and critical risk for selective reporting bias [n=16]). Conclusions and Relevance The validity of reported post-acute SARS-CoV-2 infection health outcomes in children is critically limited. None of the studies provided evidence with reasonable certainty on whether SARS-CoV-2 infection has an impact on post-acute health outcomes, let alone to what extent. Children and their families urgently need much more reliable and methodologically robust evidence to address their concerns and improve care. KEY POINTS Question How valid are the reported results on health outcomes in children after acute SARS-CoV-2 infection? Findings We identified 21 studies with only 6 using a controlled design. Reported post-acute health-outcomes were numerous and heterogeneous. The reported proportion of children with post-COVID syndrome was up to 66.5% in children with and 53.3% in children without SARS-CoV-2 infection. All studies had seriously limited validity due to critical and serious risk of bias in multiple domains. Meaning The validity of reported post-acute SARS-CoV-2 infection health outcomes in children is critically limited and methodological robust evidence is urgently needed.

OBJECTIVE Meta-analyses of epidemiologic studies have suggested that metformin may reduce cancer incidence, but randomized controlled trials did not support this hypothesis. RESEARCH DESIGN AND METHODS A retrospective cohort study, Clinical Practice Research Datalink, was designed to investigate the association between use of metformin compared with other antidiabetes medications and cancer risk by emulating an intention-to-treat analysis as in a trial. A total of 95,820 participants with type 2 diabetes who started taking metformin and other oral antidiabetes medications within 12 months of their diagnosis (initiators) were followed up for first incident cancer diagnosis without regard to any subsequent changes in pharmacotherapy. Cox proportional hazards models were used to estimate multivariable-adjusted hazard ratios (HR) and 95% CI. RESULTS A total of 51,484 individuals (54%) were metformin initiators and 18,264 (19%) were sulfonylurea initiators, and 3,805 first incident cancers were diagnosed during a median follow-up time of 5.1 years. Compared with initiators of sulfonylurea, initiators of metformin had a similar incidence of total cancer (HR 0.96; 95% CI 0.89–1.04) and colorectal (HR 0.92; 95% CI 0.76–1.13), prostate (HR 1.02; 95% CI 0.83–1.25), lung (HR 0.85; 95% CI 0.68–1.07), or postmenopausal breast (HR 1.03; 95% CI 0.82–1.31) cancer or any other cancer. CONCLUSIONS In this large study, individuals with diabetes who used metformin had a similar risk of developing cancer compared with those who used sulfonylureas.

Internet of Things (IoT) devices, once deployed, must remain secure for their entire lifetime, which can be as long as 20 years. Over this lifetime, devices must be able to update which ciphers they use to meet evolving security requirements. However, devices cannot rely on software updates for their cryptography because software implementations consume too much energy. At the same time, fixed function hardware accelerators such as an AES engine cannot support new ciphers. This paper presents Falcon, a hardware architecture for accelerating a broad range of cryptography on energy limited devices. Rather than accelerate a fixed set of current ciphers, Falcon provides a general execution engine that accelerates dominant and emerging ciphers, such as AES, Cha-Cha, SHA-256, RSA, ECC with Curve25519, as well as post-quantum ciphers such as R-LWE. For cryptography, Falcon provides the flexibility of software while reducing the energy consumption of cryptography by 5-60x compared to software. This reduction makes it feasible for IoT applications to upgrade the ciphers they use after deployment, allowing them to keep up to date with security best practices without reducing their deployment lifetime or reducing the application workload. In an application monitoring the temperature of sensitive medical supplies in hospitals, Falcon doubles the deployment lifetime (2.2x).

This study describes the policies, submission requirements, and transparency in reporting and research integrity recommendations of academic preprint servers.