A Tabletop X-Ray Tomography Instrument for Nanometer-Scale Imaging: Integration of a Scanning Electron Microscope with a Transition-Edge Sensor Spectrometer

X-ray nanotomography is a powerful tool for the characterization of nanoscale materials and structures, but is difficult to implement due to competing requirements on X-ray flux and spot size. Due to this constraint, state-of-the-art nanotomography is predominantly performed at large synchrotron facilities. Compact X-ray nanotomography tools operated in standard analysis laboratories exist, but are limited by X-ray optics and destructive sample preparation techniques. We present a laboratory-scale nanotomography instrument that achieves nanoscale spatial resolution while changing the limitations of conventional tomography tools. The instrument combines the electron beam of a scanning electron microscope (SEM) with the precise, broadband X-ray detection of a superconducting transition-edge sensor (TES) microcalorimeter. The electron beam generates a highly focused X-ray spot in a metal target, while the TES spectrometer isolates target photons with high signal-to-noise. This combination of a focused X-ray spot, energy-resolved X-ray detection, and unique system geometry enable nanoscale, element-specific X-ray imaging in a compact footprint. The proof-of-concept for this approach to X-ray nanotomography is demonstrated by imaging 160 nm features in three dimensions in a Cu-SiO2 integrated circuit, and a path towards finer resolution and enhanced imaging capabilities is discussed.Comment: The following article has been submitted to Physical Review Applie

A tabletop x-ray tomography instrument for nanometer-scale imaging: demonstration of the 1,000-element transition-edge sensor subarray

We report on the 1,000-element transition-edge sensor (TES) x-ray spectrometer implementation of the TOMographic Circuit Analysis Tool (TOMCAT). TOMCAT combines a high spatial resolution scanning electron microscope (SEM) with a highly efficient and pixelated TES spectrometer to reconstruct three-dimensional maps of nanoscale integrated circuits (ICs). A 240-pixel prototype spectrometer was recently used to reconstruct ICs at the 130 nm technology node, but to increase imaging speed to more practical levels, the detector efficiency needs to be improved. For this reason, we are building a spectrometer that will eventually contain 3,000 TES microcalorimeters read out with microwave superconducting quantum interference device (SQUID) multiplexing, and we currently have commissioned a 1,000 TES subarray. This still represents a significant improvement from the 240-pixel system and allows us to begin characterizing the full spectrometer performance. Of the 992 maximimum available readout channels, we have yielded 818 devices, representing the largest number of TES x-ray microcalorimeters simultaneously read out to date. These microcalorimeters have been optimized for pulse speed rather than purely energy resolution, and we measure a FWHM energy resolution of 14 eV at the 8.0 keV Cu K$\alpha$ line.Comment: 5 pages, 4 figures, submitted to IEEE Transactions on Applied Superconductivit

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

Embedding a Health Literacy Intervention Within Established Parenting Groups: An Australian Feasibility Study.

BACKGROUND: A significant proportion of new parents in high-income countries have lower health literacy, but few health literacy interventions exist for this group. OBJECTIVE: This study investigated the feasibility of delivering health literacy content within existing postnatal parenting groups. METHODS: Multicenter feasibility study using a seven-group pre-test post-test design. Parents older than age 16 years with children between age 4 and 26 weeks with sufficient English fluency were invited to participate in a 4-week health literacy program (four 2-hour sessions) delivered by trained facilitators (e.g., child and family health nurses). Mixed-methods evaluation was used, with quantitative data analyzed descriptively and qualitative data (e.g., focus groups, observations, interviews) analyzed using the Framework approach. KEY RESULTS: Our health literacy program was successfully delivered at six sites in New South Wales, Australia, in 2018. Our recruitment strategy was successful in reaching diverse learners (N = 73), many who were born in a country other than Australia. However, few had limited health literacy as assessed by a subjective, single-item measure, and only half completed the follow-up questionnaires. High baseline knowledge, skills, and confidence among participants limited the potential for change in these quantitative outcomes but shed light on the utility of different measurement instruments in this context. Qualitative analyses suggested that the health literacy program aligned well with the institutional objectives of child and family health services and was acceptable to learners from diverse cultural backgrounds. However, in its current form, it may be perceived as too simple for learners with higher levels of education and literacy. CONCLUSIONS: Our study has offered practical insights into the feasibility of embedding a health literacy intervention into established postnatal parenting groups and shown how program resources and facilitator training could be adapted to make the program more suitable for a range of learners and better support facilitators. [HLRP: Health Literacy Research and Practice. 2020;4(1):e67-e78.] PLAIN LANGUAGE SUMMARY: This study looked at the feasibility of delivering a 4-week health literacy program to new parents using existing postnatal parenting groups in New South Wales, Australia. Although the program was generally acceptable to learners and facilitators, this study offers several strategies to further improve the program so that it better supports facilitators and suits a wider range of learners