Publications

Efficient superscalar performance through boosting

The foremost goal of superscalar processor design is to increase performance through the exploitation of instruction-level parallelism (ILP). Previous studies have shown that speculative execution is required for high instruction per cycle (IPC) rates in non-numerical applications. The general trend has been toward supporting speculative execution in complicated, dynamically-scheduled processors. Performance, though, is more than just a high IPC rate; it also depends upon instruction count and cycle time. Boosting is an architectural technique that supports general speculative execution in simpler, statically-scheduled processors. Boosting labels speculative instructions with their control dependence information. This labelling eliminates control dependence constraints on instruction scheduling while still providng full dependence information to the hardware. We have incorporated boosting into a trace-based, global scheduling algorithm that exploits ILP without adversely affecting the instruction count of a program. We use this algorithm and estimates of the boosting hardware involved to evaluate how much speculative execution support is really necessary to achieve good performance. We find that a statically-scheduled superscalar processor using a minimal implementation of boosting can easily reach the performance of a much more complex dynamically-scheduled superscalar processor.

Limitations are not properly acknowledged in the scientific literature

Skew-tolerant domino circuits

As cycle time of chips shrinks and die size grows, clock skew measured as a fraction of the cycle time is increasing. Traditional domino circuits shown are especially sensitive because skew must be budgeted in both half-cycles. The problem with such domino pipelines is that evaluation starts when the clock connected to the first gate in the half-cycle rises but the output needs to be valid before the clock on the output latch falls. In the worst case, the evaluate clock is late and the latch clock is early, decreasing time for logic. Many designers realize that some of the overhead can be reduced by using differential domino (also called dual rail) designs. An SR latch or pipeline latch at the end of dual-rail circuits lessens sensitivity to the falling edge. Self-timed techniques eliminate clocks and clock skew, but raise new issues of control overhead, timing assumption verification, and testability. The methodology reported here boosts operating frequency by tolerating clock skew, eliminating latches from the critical path, and better balancing logic between phases of the pipeline.

Systematic evaluation of environmental and behavioural factors associated with all-cause mortality in the United States National Health and Nutrition Examination Survey

Abstract Background Environmental and behavioural factors are thought to contribute to all-cause mortality. Here, we develop a method to systematically screen and validate the potential independent contributions to all-cause mortality of 249 environmental and behavioural factors in the National Health and Nutrition Examination Survey (NHANES). Methods We used Cox proportional hazards regression to associate 249 factors with all-cause mortality while adjusting for sociodemographic factors on data in the 1999–2000 and 2001–02 surveys (median 5.5 follow-up years). We controlled for multiple comparisons with the false discovery rate (FDR) and validated significant findings in the 2003–04 survey (median 2.8 follow-up years). We selected 249 factors from a set of all possible factors based on their presence in both the 1999–2002 and 2003–04 surveys and linkage with at least 20 deceased participants. We evaluated the correlation pattern of validated factors and built a multivariable model to identify their independent contribution to mortality. Results We identified seven environmental and behavioural factors associated with all-cause mortality, including serum and urinary cadmium, serum lycopene levels, smoking (3-level factor) and physical activity. In a multivariable model, only physical activity, past smoking, smoking in participant’s home and lycopene were independently associated with mortality. These three factors explained 2.1% of the variance of all-cause mortality after adjusting for demographic and socio-economic factors. Conclusions Our association study suggests that, of the set of 249 factors in NHANES, physical activity, smoking, serum lycopene and serum/urinary cadmium are associated with all-cause mortality as identified in previous studies and after controlling for multiple hypotheses and validation in an independent survey. Whereas other NHANES factors may be associated with mortality, they may require larger cohorts with longer time of follow-up to detect. It is possible to use a systematic association study to prioritize risk factors for further investigation.

Nationwide Population Science

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Contents Vol. 80, No. 4, 2015

Nail Pigmentation and Fatigue in a 39‐Year‐Old Woman

Diagnosis: HIV-1 infection and longitudinal melanonychia. This diagnosis was suggested by the findings of the physical examination (figure 1) and laboratory data in conjunction with the sexual history of the patient's husband, who admitted on further questioning that he was sexually promiscuous with tourists and that he was participating in orgies involving intercourse with persons of both sexes. The patient had positive results of an HIV-1 ELISA and a Western blot assay. Her CD4 cell count was 116 cells/mm3, and her virus load was 185,000 copies/mL, as determined by RT-PCR (Amplicor; Roche). Subsequently, her husband also tested positive for HIV-1 infection. Longitudinal melanonychia may occasionally occur in the absence of other disease, particularly in dark-skinned subjects [1, 2], but several pathologic associations have also been described. Common causes include the following: melanoma [1, 2]; benign nevi [2]; trauma that results in subungual hematoma [2]; hydroxyurea [2, 3]; adriamycin, cyclophosphamide, and polychemotherapy [1]; antimalarials [2]; and tetracyclines [2]. Less frequent causes include onychomycosis [2], nonmelanocytic tumors [2], endocrinopathy [1], onychotillomania [4], sub ngual keratosis of the nail bed [5], Laugier-Hunziker syndrome (mela onychia with macular pigmentation of the lips and buccal mucosa) [2], pregnancy [6], and systemic lupus erythematosus [7]. In HIV-l-infected patients, nail pigmentation is typically seen after the introduction of zidovudine therapy. This is a common and well-described occurrence, especially in darkskinned individuals [8-13]. On the other hand, relatively few reports have been published that link nail color changes with HIV-1 infection in patients who are not receiving antiretroviral ther py [8, 1, 14-18]. Longitudinal melanonychia has been associated with diffuse mucocutaneous pigmentation [15]. Nail

Genome-wide association studies for complex traits: consensus, uncertainty and challenges

Early or Deferred Zidovudine Therapy in HIV-Infected Patients without an AIDS-Defining Illness

Early initiation of zidovudine therapy offers a benefit that decreases over time. Symptomatic patients experience a larger benefit than asymptomatic patients. The implications beyond 3 years of follow-up remain unknown.

Micro-management of Risk in a Trust-Based Billing System

The Accuracy of the Patient Health Questionnaire-9 Algorithm for Screening to Detect Major Depression: An Individual Participant Data Meta-Analysis

Background: Screening for major depression with the Patient Health Questionnaire-9 (PHQ-9) can be done using a cutoff or the PHQ-9 diagnostic algorithm. Many primary studies publish results for only one approach, and previous meta-analyses of the algorithm approach included only a subset of primary studies that collected data and could have published results. Objective: To use an individual participant data meta-analysis to evaluate the accuracy of two PHQ-9 diagnostic algorithms for detecting major depression and compare accuracy between the algorithms and the standard PHQ-9 cutoff score of ≥10. Methods: Medline, Medline In-Process and Other Non-Indexed Citations, PsycINFO, Web of Science (January 1, 2000, to February 7, 2015). Eligible studies that classified current major depression status using a validated diagnostic interview. Results: Data were included for 54 of 72 identified eligible studies (n participants = 16,688, n cases = 2,091). Among studies that used a semi-structured interview, pooled sensitivity and specificity (95% confidence interval) were 0.57 (0.49, 0.64) and 0.95 (0.94, 0.97) for the original algorithm and 0.61 (0.54, 0.68) and 0.95 (0.93, 0.96) for a modified algorithm. Algorithm sensitivity was 0.22-0.24 lower compared to fully structured interviews and 0.06-0.07 lower compared to the Mini International Neuropsychiatric Interview. Specificity was similar across reference standards. For PHQ-9 cutoff of ≥10 compared to semi-structured interviews, sensitivity and specificity (95% confidence interval) were 0.88 (0.82-0.92) and 0.86 (0.82-0.88). Conclusions: The cutoff score approach appears to be a better option than a PHQ-9 algorithm for detecting major depression.

Are amoxycillin and folate inhibitors as effective as other antibiotics for acute sinusitis? A meta-analysis

Amoxycillin and folate inhibitors are essentially as effective as more expensive antibiotics for the initial treatment of uncomplicated acute sinusitis. Small differences in efficacy may exist, but are unlikely to be clinically important.

Lack of evidence to favor specific preventive interventions in psychosis: a network meta‐analysis

Preventing psychosis in patients at clinical high risk may be a promising avenue for pre‐emptively ameliorating outcomes of the most severe psychiatric disorder. However, information on how each preventive intervention fares against other currently available treatment options remains unavailable. The aim of the current study was to quantify the consistency and magnitude of effects of specific preventive interventions for psychosis, comparing different treatments in a network meta‐analysis. PsycINFO, Web of Science, Cochrane Central Register of Controlled Trials, and unpublished/grey literature were searched up to July 18, 2017, to identify randomized controlled trials conducted in individuals at clinical high risk for psychosis, comparing different types of intervention and reporting transition to psychosis. Two reviewers independently extracted data. Data were synthesized using network meta‐analyses. The primary outcome was transition to psychosis at different time points and the secondary outcome was treatment acceptability (dropout due to any cause). Effect sizes were reported as odds ratios and 95% confidence intervals (CIs). Sixteen studies (2,035 patients, 57% male, mean age 20.1 years) reported on risk of transition. The treatments tested were needs‐based interventions (NBI); omega‐3 + NBI; ziprasidone + NBI; olanzapine + NBI; aripiprazole + NBI; integrated psychological interventions; family therapy + NBI; D‐serine + NBI; cognitive behavioural therapy, French & Morrison protocol (CBT‐F) + NBI; CBT‐F + risperidone + NBI; and cognitive behavioural therapy, van der Gaag protocol (CBT‐V) + CBT‐F + NBI. The network meta‐analysis showed no evidence of significantly superior efficacy of any one intervention over the others at 6 and 12 months (insufficient data were available after 12 months). Similarly, there was no evidence for intervention differences in acceptability at either time point. Tests for inconsistency were non‐significant and sensitivity analyses controlling for different clustering of interventions and biases did not materially affect the interpretation of the results. In summary, this study indicates that, to date, there is no evidence that any specific intervention is particularly effective over the others in preventing transition to psychosis. Further experimental research is needed.

Excess Significance Bias in the Literature on Brain Volume Abnormalities

There are too many studies with statistically significant results in the literature on brain volume abnormalities. This pattern suggests strong biases in the literature, with selective outcome reporting and selective analyses reporting being possible explanations.

Synthetic aperture confocal imaging

Confocal microscopy is a family of imaging techniques that employ focused patterned illumination and synchronized imaging to create cross-sectional views of 3D biological specimens. In this paper, we adapt confocal imaging to large-scale scenes by replacing the optical apertures used in microscopy with arrays of real or virtual video projectors and cameras. Our prototype implementation uses a video projector, a camera, and an array of mirrors. Using this implementation, we explore confocal imaging of partially occluded environments, such as foliage, and weakly scattering environments, such as murky water. We demonstrate the ability to selectively image any plane in a partially occluded environment, and to see further through murky water than is otherwise possible. By thresholding the confocal images, we extract mattes that can be used to selectively illuminate any plane in the scene.

Perspective: Limiting Dependence on Nonrandomized Studies and Improving Randomized Trials in Human Nutrition Research: Why and How

Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials

Time-Varying Risk of Death After SARS-CoV-2-Infection in Long-Term Care Facility Residents: A Matched Cohort Study

Abstract Background SARS-CoV-2 confers high risk of short-term death in residents of long-term care (LTC) facilities, but longer-term risk among survivors is unclear. Methods We extended the follow-up period of a previous, propensity score-matched retrospective cohort study based on the Swedish Senior Alert register. N=3731 LTC residents with documented SARS-CoV-2 until 15 September 2020 were matched to 3731 uninfected controls using time-dependent propensity scores on age, sex, health status, comorbidities, and prescription medications. In a sensitivity analysis, matching included also geographical region and Senior Alert registration time. The outcome was all-cause mortality over 8 months (until October 24, 2020). The absolute risk of death was examined using Kaplan-Meier plots. Hazard ratios (HR) for death over time were estimated using flexible parametric models with restricted cubic splines. Cox regression was used to estimate HRs and 95% confidence intervals (CIs) in 30-day intervals of follow-up until 210 days. Results The median age was 87 years and 65% were women. Excess mortality was highest 5 days after documented infection (HR 19.1, 95% CI, 14.6-24.8), after which excess mortality decreased. From the second month onwards, mortality rate became lower in infected residents than controls. The HR for death during days 61-210 of follow-up was 0.41 in the main analysis (95% CI, 0.34-0.50) and 0.76 (95% CI, 0.62-0.93) in the sensitivity analysis. Median survival of uninfected controls was 1.6 years, which was much lower than the national life expectancy in Sweden at age 87 (5.05 years in men, 6.07 years in women). Conclusions No excess mortality was observed in LTC residents who survived the acute SARS-CoV-2 infection. Life expectancy of uninfected residents was much lower than that of the general population of the same age and sex. This suggests that LTC resident status should be accounted for in years-of-life-lost estimates for COVID-19 burden of disease calculations. Impact statement We certify that this work is novel. This research adds to the literature by showing there was no excess mortality observed in long-term care facility residents who survived the acute SARS-CoV-2 infection, and that life expectancy of uninfected residents was much lower than that of the general population of same age and sex. This has major repercussions for estimation of years of life lost in infected long term care facility residents. Key points SARS-CoV-2 infection sharply increased mortality risk among residents of long-term care (LTC) facilities in the first month. After the first month, the mortality risk in infected residents rapidly returned to baseline and dropped below the mortality risk of uninfected controls, where it remained lower for 8 months of follow-up. Median survival of uninfected controls was 1.6 years, which was much lower than national life expectancy in Sweden at age 87. Why does this matter? Whereas LTC residents who recover from SARS-CoV-2 infection may be concerned about having residual debilitation caused by the infection, we found no excess mortality was in those who survived the acute infection. Because life expectancy of uninfected residents was much lower than that of the general population of same age and sex, LTC resident status should be accounted for in estimations of years of life lost.