Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine

Previous studies demonstrated that ataxia telangiectasia mutated- and Rad3-related (ATR) kinase and its downstream target checkpoint kinase 1 (Chk1) facilitate survival of cells treated with nucleoside analogs and other replication inhibitors. Recent results also demonstrated that Chk1 is depleted when cells are treated with heat shock protein 90 (Hsp90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). The present study examined the effects of 17-AAG and its major metabolite, 17-aminogeldanamycin (17-AG), on Chk1 levels and cellular responses to cytarabine in human acute myelogenous leukemia (AML) cell lines and clinical isolates. Cytarabine, at concentrations as low as 30 nM, caused activating phosphorylation of Chk1, loss of the phosphatase Cdc25A, and S-phase slowing. Conversely, treatment with 100 to 300 nM 17-AAG for 24 hours caused Chk1 depletion that was accompanied by diminished cytarabine-induced S-phase accumulation, decreased Cdc25A degradation, and enhanced cytotoxicity as measured by inhibition of colony formation and induction of apoptosis. Additional studies demonstrated that small inhibitory RNA (siRNA) depletion of Chk1 also sensitized cells to cytarabine, whereas disruption of the phosphatidylinositol 3-kinase (PI3k) signaling pathway, which is also blocked by Hsp90 inhibition, did not. Collectively, these results suggest that treatment with 17-AAG might represent a means of reversing checkpoint-mediated cytarabine resistance in AML.     

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

Predictors and Outcomes of Frequent Emergency Department Users

OBJECTIVE: To identify predictors and outcomes associated with frequent emergency department (ED) users. METHODS: Cross-sectional intake surveys, medical chart reviews, and telephone follow-up interviews of patients presenting with selected chief complaints were performed at five urban EDs during a one-month study period in 1995. Frequent use was defined by four or more self-reported, prior ED visits. Multivariate logistic regression identified predictors of frequent ED visitors from five domains (demographics, health status, health access, health care preference, and severity of acute illness). Associations between high use and selected outcomes were assessed with logistic regression models. RESULTS: All study components were completed by 2,333 of 3,455 eligible patients (67.5%). Demographics predicting frequent use included being a single parent, single or divorced marital status, high school education or less, and income of less than $10,000 (1995). Health status predictors included hospitalization in the preceding three months, high ratings of psychological distress, and asthma. Health access predictors included identifying an ED or a hospital clinic as the primary care site, having a primary care physician (PCP), and visiting a PCP in the past month. Choosing the ED for free care was the only health preference predictive of heavy use. Illness severity measures were higher in frequent visitors, although these were not independently predictive in the multivariate model. Outcomes correlated with heavy use include increased hospital admissions, higher rates of ED return visits, and lower patient satisfaction, but not willingness to return to the ED or follow-up with a doctor. CONCLUSIONS: Frequent ED visits are associated with socioeconomic distress, chronic illness, and high use of other health resources. Efforts to reduce ED visits require addressing the unique needs of these patients in the emergency and primary care settings.     

Evaluation of amphotericin B interpretive breakpoints for Candida bloodstream isolates by correlation with therapeutic outcome

One hundred seven Candida bloodstream isolates (51 C. albicans, 24 C. glabrata, 13 C. parapsilosis, 13 C. tropicalis, 2 C. dubliniensis, 2 C. krusei, and 2 C. lusitaniae strains) from patients treated with amphotericin B alone underwent in vitro susceptibility testing against amphotericin B using five different methods. Fifty-four isolates were from patients who failed treatment, defined as death 7 to 14 days after the incident candidemia episode, having persistent fever of >or=5 days' duration after the date of the incident candidemia, or the recurrence of fever after two consecutive afebrile days while on antifungal treatment. MICs were determined by using the Clinical Laboratory Standards Institute (formally National Committee for Clinical Laboratory Standards) broth microdilution procedure with two media and by using Etest. Minimum fungicidal concentrations (MFCs) were also measured in two media. Broth microdilution tests with RPMI 1640 medium generated a restricted range of MICs (0.125 to 1 microg/ml); the corresponding MFC values ranged from 0.5 to 4 microg/ml. Broth microdilution tests with antibiotic medium 3 produced a broader distribution of MIC and MFC results (0.015 to 0.25 microg/ml and 0.06 to 2 microg/ml, respectively). Etest produced the widest distribution of MICs (0.094 to 2 microg/ml). However, none of the test formats studied generated results that significantly correlated with therapeutic success or failure.     

The palliation of esophageal carcinoma

There has been limited success in treating esophageal carcinoma over the last 40 years. Despite improvements in radiation therapy, surgical approaches, and chemotherapy, the mortality rate from this disease has shown little change. In the majority of patients, palliation is the major issue that must be addressed. A wide variety of modalities are currently available for this purpose. The lack of comparative studies of these modalities limits our ability to make specific general recommendations. An approach to patients with esophageal carcinoma should be multidisciplinary, using available expertise to choose from the wide variety of available modalities, both established and new. Major efforts are needed to collect prospective data that will allow specific recommendations to be made regarding the best, most effective, and least expensive, methods of palliation while new methods of treatment for cure are sought.     

Hand‐foot‐skin reaction related to use of the multikinase inhibitor sorafenib and hard orthotics

Hand‐foot‐skin reaction is a distinct clinical condition arising in association with the use of multikinase inhibitors, including sorafenib. Because multikinase inhibitors are increasingly being used in children with cancer, recognition of this previously unfamiliar condition is of importance to pediatric dermatologists. We describe the diagnosis and successful treatment of a case of hand‐foot‐skin reaction in a child taking sorafenib for an unresectable desmoid tumor.     

Functional imaging of pain in patients with primary fibromyalgia

OBJECTIVE: To examine the function of the nociceptive system in patients with fibromyalgia (FM) using functional magnetic resonance imaging (fMRI). METHODS: Two groups of women, 9 with FM and 9 pain-free, volunteered to participate. In Experiment 1, we assessed psychophysical responses to painful stimuli and prepared participants for fMRI testing. For Experiment 2, subjects underwent fMRI scanning while receiving painful and nonpainful heat stimuli. Conventional and functional MR images were acquired using a 1.5 T MR scanner. Scanning occurred over 5 conditions. Condition 1 served as a practice session (no stimuli). Conditions 2 and 5 consisted of nonpainful warm stimuli. Conditions 3 and 4 consisted of an absolute thermal pain stimulus (47 degrees C) and a perceptually equivalent pain stimulus delivered in counterbalanced order. RESULTS: Experiment 1 indicated that subjects with FM were significantly more sensitive to experimental heat pain than controls (p < 0.001). In Experiment 2, fMRI data indicated that the FM group exhibited greater activity than controls over multiple brain regions in response to both nonpainful and painful stimuli (p < 0.01). Specifically, in response to nonpainful warm stimuli, FM subjects had significantly greater activity than controls in prefrontal, supplemental motor, insular, and anterior cingulate cortices (p < 0.01). In response to painful stimuli, FM subjects had greater activity in the contralateral insular cortex (p < 0.01). Data from the practice session indicated brain activity in pain-relevant areas for the FM group but not for controls. CONCLUSION: Our results provide further evidence for a physiological explanation for FM pain.