Hyperpolarized product selective saturating‐excitations for determination of changes in metabolic reaction rates in real‐time

Investigation of hyperpolarized substrate metabolism has been showing utility in real‐time determination of in‐cell and in vivo enzymatic activities. Intracellular reaction rates may vary during the course of a measurement, even on the very short time scales of visibility on hyperpolarized MR, due to many factors such as the availability of the substrate and co‐factors in the intracellular space. Despite this potential variation, the kinetic analysis of hyperpolarized signals typically assumes that the same rate constant (and in many cases, the same rate) applies throughout the course of the reaction as observed via the build‐up and decay of the hyperpolarized signals. We demonstrate here an acquisition approach that can null the need for such an assumption and enable the detection of instantaneous changes in the rate of the reaction during an ex vivo hyperpolarized investigation, (i.e. in the course of the decay of one hyperpolarized substrate dose administered to a viable tissue sample ex vivo). This approach utilizes hyperpolarized product selective saturating‐excitation pulses. Similar pulses have been previously utilized in vivo for spectroscopic imaging. However, we show here favorable consequences to kinetic rate determinations in the preparations used. We implement this acquisition strategy for studies on perfused tissue slices and develop a theory that explains why this particular approach enables the determination of changes in enzymatic rates that are monitored via the chemical conversions of hyperpolarized substrates. Real‐time changes in intracellular reaction rates are demonstrated in perfused brain, liver, and xenograft breast cancer tissue slices and provide another potential differentiation parameter for tissue characterization.     

Mask wearing in community settings reduces SARS-CoV-2 transmission

The effectiveness of mask wearing at controlling severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission has been unclear. While masks are known to substantially reduce disease transmission in healthcare settings [D. K. Chu et al., Lancet 395, 1973–1987 (2020); J. Howard et al., Proc. Natl. Acad. Sci. U.S.A. 118, e2014564118 (2021); Y. Cheng et al., Science eabg6296 (2021)], studies in community settings report inconsistent results [H. M. Ollila et al., medRxiv (2020); J. Brainard et al., Eurosurveillance 25, 2000725 (2020); T. Jefferson et al., Cochrane Database Syst. Rev. 11, {"type":"entrez-nucleotide","attrs":{"text":"CD006207","term_id":"30322945","term_text":"CD006207"}}CD006207 (2020)]. Most such studies focus on how masks impact transmission, by analyzing how effective government mask mandates are. However, we find that widespread voluntary mask wearing, and other data limitations, make mandate effectiveness a poor proxy for mask-wearing effectiveness. We directly analyze the effect of mask wearing on SARS-CoV-2 transmission, drawing on several datasets covering 92 regions on six continents, including the largest survey of wearing behavior (n= 20 million) [F. Kreuter et al., https://gisumd.github.io/COVID-19-API-Documentation (2020)]. Using a Bayesian hierarchical model, we estimate the effect of mask wearing on transmission, by linking reported wearing levels to reported cases in each region, while adjusting for mobility and nonpharmaceutical interventions (NPIs), such as bans on large gatherings. Our estimates imply that the mean observed level of mask wearing corresponds to a 19% decrease in the reproduction number R. We also assess the robustness of our results in 60 tests spanning 20 sensitivity analyses. In light of these results, policy makers can effectively reduce transmission by intervening to increase mask wearing.

Face masks are one of the most prominent interventions against COVID-19, with very high uptake in most countries (1). However, global mask wearing fell substantially in 2021, even in countries with low vaccination rates (Fig. 1). Given ongoing epidemics, establishing the effectiveness of mask wearing in community settings is critical. The following sections review past work on the effectiveness of mask wearing in different settings and at different scales.Open in a separate windowFig. 1.Reported mask wearing in countries with <40% of population fully vaccinated, as of 1 October 2021 [wearing from the UMD/Facebook survey (1); vaccinations from ref. 2]. The y axis is the proportion who reported that, over the last week, they wore masks most or all of the time in public spaces.In the context of healthcare, N95 masks (as defined by ref. 3) work well when worn properly by trained users—reducing transmission of coronaviruses including severe acute respiratory coronavirus syndrome 2 (SARS-CoV-2) by at least half (4, 5). Cheng et al. (6) find that ideal surgical masking (7, 8) of a noninfected person corresponds to a 65 to 75% reduction in their risk of COVID-19.However, the effect of mask wearing in small-scale community settings is more difficult to detect.In particular, four meta-analyses have summarized studies on respiratory infections, conducted in community settings (4, 9–11). They estimate mean decreases in infection risk between 4% and 15% for surgical masks, but with large uncertainty: Individual results ranged from a 7% increase in infection risk to a 61% decrease in infection risk. In addition, few of these studies are randomized controlled trials (RCTs), and those that are RCTs have considerable issues: Bungaard et al. (12) found a small, nonsignificant reduction in infection risk. Abaluck et al. (13), found a significant, 8.6% decrease in symptomatic seropositivity linked to mask wearing. However, limitations of the study included a requirement for unblinded participants to self-report symptoms before testing, use of an antibody test with a very low 5 d sensitivity, and unclear generalization from the specific context (rural villages in Bangladesh).We focus on the effects of mask wearing or mandates (i.e., legal requirements to wear a mask) on transmission in large connected populations. To study mask impacts on transmission, many studies use the timing of mask mandates as a proxy for sharp changes in the level of mask wearing. Some such studies have inferred limited or inconclusive effects in cross-country analyses (14) and within-country studies (15), while others find cross-country evidence that mask mandates and recommendations lead to decreased transmission and mortality (16, 17).Other analyses provide evidence for reduced case growth following subnational mandates within countries such as the United States (18–20) and Germany (21). A potential explanation for the inconsistency and uncertainty of these results is that data on national mandate timing may be poorly suited for analyzing the effects of mask wearing on transmission.Epidemiological studies often use government mask mandates as a proxy for mask wearing. However, the existing literature on the relationship between mandates and actual levels of mask wearing has shown surprisingly weak effects. For example, studying US states, ref. 22 failed to find a statistically significant relationship between mandates and subsequent wearing, while other studies found postmandate increases in wearing of just 13% (23) and 23% (24). Betsch et al. (25) find a ∼40% increase in wearing after local mandates in Germany, but no other study finds a comparably large increase. Given that the link between mandates and wearing is surprisingly weak, it is likely that the link between mandates and transmission is difficult to detect. Three additional factors lead us to suspect that a link between mandates and transmission would be difficult to detect. First, introducing a mandate is a coarse, one-off event that necessarily loses signal by not tracking day-to-day changes in mask wearing. We also have fewer data on mandates: Less than half of the regions we study enforced any mandate during the study period. Second, past studies treat mandates as a binary on/off intervention that is fully implemented at a single point in time. However, modeling the effect of mandates as an instantaneous change in the reproduction number or mortality fails to capture changes in wearing behavior following the announcement of a mandate but before its enforcement (21). Nor does it account for gradual change in behavior after the implementation of a mandate. Finally, the circumstances of mandate policies are highly heterogeneous, both in terms of the preexisting level of voluntary wearing at the time of implementation and in terms of how exactly they are defined, enforced, and complied with. Consequently, averaging the international effect of mandates based on coarse data is unlikely to provide a useful summary of heterogeneous mandate effects. Importantly, these arguments point to the link between mandates and transmission being difficult to detect, not that it is absent.Because of these difficulties in studying the effect of mandates, we instead focus on estimating the effect of mask wearing on transmission, using a large (n = 19.97 million) global survey of self-reported mask wearing (1). Two other studies estimate mask effectiveness from self-reports: In their study of 24 countries, Aravindakshan et al. (26) use YouGov wearing data to infer an overall 3.9 to 10% relative decrease in case growth rate from whole population mask wearing. Rader et al. (22) study US states using a novel SurveyMonkey wearing dataset to infer a ∼10% decrease in transmission between the lowest and highest empirical quartiles of wearing (a 50 to 75% increase in wearing). Rader et al. use data limited to 12 US states during June–July 2020. Our data are richer: We study 56 countries on six continents, and our inferential analyses span May–September 2020.Our analysis goes further than past work in the quality of wearing data—100 times the sample size, with random sampling and poststratification—the geographical scope, the use of a semimechanistic infection model, the incorporation of uncertainty into epidemiological parameters, and the robustness of our results (59 sensitivity tests). See

Lack of Evidence to Support Thromboprophylaxis in Hospitalized Medical Patients with Cancer

Background

The administration of anticoagulant thromboprophylaxis for all patients with cancer who are hospitalized for acute medical illness is considered standard practice and strongly recommended in clinical guidelines. These recommendations are extrapolated from randomized controlled prophylaxis trials not specifically conducted in cancer cohorts. Because hospitalized patients with cancer constitute a unique population with increased risk of venous thromboembolic events and major hemorrhage, validation of the efficacy and safety of primary thromboprophylaxis in this population is critical. We sought to summarize the rates of venous thromboembolic events and major bleeding episodes among hospitalized patients with cancer who were receiving anticoagulant therapy compared with placebo.

Methods

A systematic literature search strategy was conducted using MEDLINE, EMBASE, and the Cochrane Register of Controlled Trials. Two reviewers independently extracted data onto standardized forms. The primary end points were all venous thromboembolic events. Secondary end points included major bleeding episodes and symptomatic venous thromboembolic events. Pooled analysis with relative risk using a random effect model was used as the primary measurement.

Results

A total of 242 citations were identified by the literature search. Of these, 3 placebo-controlled randomized trials included venous thromboembolic events as a primary outcome and were analyzed according to cancer subgroups. The pooled relative risk of venous thromboembolic events was 0.91 (95% confidence interval, 0.21-4.0; I²: 68%) among hospitalized patients with cancer who were receiving thromboprophylaxis compared with placebo. None of the trials reported the rates of symptomatic venous thromboembolic events or major bleeding episodes according to cancer status.

Conclusions

The risks and benefits of primary thromboprophylaxis with anticoagulant therapy in hospitalized patients with cancer are not known. This is especially relevant because numerous Medicare-type pay-for-performance incentives mandate prophylaxis specifically in patients with cancer.     

Risk of recurrent venous thromboembolism among young women after a first event while exposed to combined oral contraception versus not exposed to: A cohort study

The risk of recurrent venous thromboembolism (VTE) in young women after a first oestrogen contraception associated VTE episode is unknown. This uncertainty has an impact on the decision whether to stop anticoagulant treatment. Our objective was to assess the risk of recurrent VTE in women after a first VTE episode on oestrogen contraception. This was a prospective cohort study in which we consecutively enrolled between 1992 and 2011 all women under 50 years with a first objectively confirmed VTE. The incidence of recurrent VTE during follow-up after stopping anticoagulation was compared between women users and non-users of combined oral contraception (COC) at the time of index VTE. Of the 241 women aged 50 or younger seen for a first VTE and followed-up after stopping anticoagulation, there were 180 COC-users and 61 non-users. Median duration of follow-up off-anticoagulants was 66 months (interquartile range: 33–103). There were 14 recurrences in COC-users and 5 cases in non-users. No significant association was found between exposure to COC and the incidence of recurrent VTE after adjustment for age or after restricting the analysis to major unprovoked VTE: incidence rate of recurrence 17.9/1,000/year (95% CI: 9.6-33.2) in women with COC as compared with 17.6/1,000/year (95% CI: 6.6-47) with an incidence ratio of 0.7 (95% CI: 0.2-2.4, p = 0.59). The risk of recurrent VTE is low in young women after a first VTE. However, this risk is not significantly lower in women after a first VTE while exposed to combined oral contraception.     

Everyday memory and laboratory memory tests: general function predictors in schizophrenia and remitted depression

This study was designed to compare neuropsychological memory measures ("laboratory memory tests") and an everyday memory measure in patients with schizophrenia, patients with major depression, and normal controls. Patients with schizophrenia ( N= 68) treated with typical (N = 33) or atypical ( N= 35) neuroleptics, patients with major depression (N = 30), and a control group (N = 36) were evaluated with clinical measures (Positive and Negative Syndrome Scale and Hamilton Depression Rating Scale), laboratory memory tests (Digit-Span, Paired-Associates, Rey Complex Figure Test, and Digit-Symbol), everyday memory test (RMBT), and the Global Assessment of Functioning (GAF). The schizophrenia group had a significantly lower level of performance in everyday memory and general function but not in laboratory memory tests. Verbal and everyday memory measures were correlated with general function. The diagnosis rather than current symptoms (in remission) contributed to test variance and was correlated with performance on everyday memory and general function tests. Everyday memory and verbal memory were good predictors of general function in schizophrenic and depressive patients in the remitted phase. However, the advantages of these tests over laboratory memory tests need to be further investigated in larger and more representative samples.     

Apolipoprotein E4 enhances brain inflammation by modulation of the NF-κB signaling cascade

Apolipoprotein E4 (apoE4), the major genetic risk factor of Alzheimer's disease (AD), is associated with enhanced brain inflammation. Genome-wide gene expression profiling was employed to study the effects of apoE genotype on hippocampal gene expression in LPS-treated mice, transgenic for either apoE4 or the AD benign allele, apoE3. This revealed that the expression of inflammation-related genes following intracerebroventricular injection of LPS was significantly higher and more prolonged in apoE4 than in apoE3 transgenic mice. Clustering analysis revealed gene clusters which responded differently in apoE4 and apoE3 mice and were significantly enriched in NF-kappaB response elements. Direct measurement of NF-kappaB-regulated genes revealed that their extent of activation was greater in the apoE4 mice. Immunohistochemistry experiments revealed that microglial and NF-kappaB activation were more pronounced in apoE4 than in apoE3 mice. These findings suggest that the increased brain inflammation in apoE4 mice is related to disregulation of NF-kappaB signaling pathway.