Abstract
Many bacteria that live in contact with eukaryotic hosts, whether as symbionts or as pathogens, have evolved mechanisms that manipulate host cell behaviour to their benefit. One such ...mechanism, the type III secretion system, is employed by Gram-negative bacterial species to inject effector proteins into host cells. This function is reflected by the overall shape of the machinery, which resembles a molecular syringe. Despite the simplicity of the concept, the type III secretion system is one of the most complex known bacterial nanomachines, incorporating one to more than hundred copies of up to twenty different proteins into a multi-MDa transmembrane complex. The structural core of the system is the so-called needle complex that spans the bacterial cell envelope as a tripartite ring system and culminates in a needle protruding from the bacterial cell surface. Substrate targeting and translocation are accomplished by an export machinery consisting of various inner membrane embedded and cytoplasmic components. The formation of such a multimembrane-spanning machinery is an intricate task that requires precise orchestration. This review gives an overview of recent findings on the assembly of type III secretion machines, discusses quality control and recycling of the system and proposes an integrated assembly model.
This review discusses the assembly of the type III secretion injectisome, a cell envelope spanning macromolecular machine used by Gram-negative bacteria to translocate bacterial effector proteins into host cells.
The aim of this study was to investigate the impact of menopausal symptoms and menopausal symptom severity on health-related quality of life (HRQoL), work impairment, healthcare utilization, and ...costs.
Data from the 2005 United States National Health and Wellness Survey were used, with only women 40-64 years without a history of cancer included in the analyses (N=8,811). Women who reported experiencing menopausal symptoms (n=4,116) were compared with women not experiencing menopausal symptoms (n=4,695) on HRQoL, work impairment, and healthcare utilization using regression modeling (and controlling for demographics and health characteristic differences). Additionally, individual menopausal symptoms were used as predictors of outcomes in a separate set of regression models.
The mean age of women in the analysis was 49.8 years (standard deviation,±5.9). Women experiencing menopausal symptoms reported significantly lower levels of HRQoL and significantly higher work impairment, and healthcare utilization than women without menopausal symptoms. Depression, anxiety, and joint stiffness were symptoms with the strongest associations with health outcomes.
Menopausal symptoms can be a significant humanistic and economic burden on women in middle age.
Background & Aims
Hepatocellular carcinoma (HCC) is the second most common cause of cancer deaths worldwide. The global HCC BRIDGE study was a multiregional, large‐scale, longitudinal cohort study ...undertaken to improve understanding of real‐life management of patients with HCC, from diagnosis to death.
Methods
Data were collected retrospectively from January 2005 to September 2012 by chart reviews of eligible patients newly diagnosed with HCC at participating institutions.
Results
Forty‐two sites in 14 countries contributed final data for 18 031 patients. Asia accounted for 67% of patients, Europe for 20% and North America for 13%. As expected, the most common risk factor was hepatitis C virus in North America, Europe and Japan, and hepatitis B virus in China, South Korea and Taiwan. The most common Barcelona Clinic Liver Cancer stage at diagnosis was C in North America, Europe, China and South Korea, and A in Taiwan and Japan. Across all stages, first HCC treatment was most frequently transarterial chemoembolization in North America, Europe, China and South Korea, percutaneous ethanol injection or radiofrequency ablation in Japan and resection in Taiwan. Survival from first HCC treatment varied significantly by region, with median overall survival not reached for Taiwan and 60, 33, 31, 24 and 23 months for Japan, North America, South Korea, Europe and China respectively (P < 0.0001).
Conclusions
Initial results from the BRIDGE study confirm previously reported regional trends in patient demographic characteristics and HCC risk factors, document the heterogeneity of treatment approaches across regions/countries and underscore the need for earlier HCC diagnosis worldwide.
Abstract Background Economic evaluations often measure an intervention effect with mean overall survival (OS). Emerging types of cancer treatments offer the possibility of being “cured” in that ...patients can become long-term survivors whose risk of death is the same as that of a disease-free person. Describing cured and noncured patients with one shared mean value may provide a biased assessment of a therapy with a cured proportion. Objective The purpose of this article is to explain how to incorporate the heterogeneity from cured patients into health economic evaluation. Methods We analyzed clinical trial data from patients with advanced melanoma treated with ipilimumab (Ipi; n = 137) versus glycoprotein 100 (gp100; n = 136) with statistical methodology for mixture cure models. Both cured and noncured patients were subject to background mortality not related to cancer. Results When ignoring cured proportions, we found that patients treated with Ipi had an estimated mean OS that was 8 months longer than that of patients treated with gp100. Cure model analysis showed that the cured proportion drove this difference, with 21% cured on Ipi versus 6% cured on gp100. The mean OS among the noncured cohort patients was 10 and 9 months with Ipi and gp100, respectively. The mean OS among cured patients was 26 years on both arms. When ignoring cured proportions, we found that the incremental cost-effectiveness ratio (ICER) when comparing Ipi with gp100 was $324,000/quality-adjusted life-year (QALY) (95% confidence interval $254,000–$600,000). With a mixture cure model, the ICER when comparing Ipi with gp100 was $113,000/QALY (95% confidence interval $101,000–$154,000). Conclusions This analysis supports using cure modeling in health economic evaluation in advanced melanoma. When a proportion of patients may be long-term survivors, using cure models may reduce bias in OS estimates and provide more accurate estimates of health economic measures, including QALYs and ICERs.
Export of proteins through type III secretion systems is critical for motility and virulence of many major bacterial pathogens. Three putative integral membrane proteins (FliP, FliQ, FliR) are ...suggested to form the core of an export gate in the inner membrane, but their structure, assembly and location within the final nanomachine remain unclear. Here, we present the cryoelectron microscopy structure of the Salmonella Typhimurium FliP-FliQ-FliR complex at 4.2 Å. None of the subunits adopt canonical integral membrane protein topologies, and common helix-turn-helix structural elements allow them to form a helical assembly with 5:4:1 stoichiometry. Fitting of the structure into reconstructions of intact secretion systems, combined with cross-linking, localize the export gate as a core component of the periplasmic portion of the machinery. This study thereby identifies the export gate as a key element of the secretion channel and implies that it primes the helical architecture of the components assembling downstream.
In quantum sensing, precision is typically limited by the maximum time interval over which phase can be accumulated. Memories have been used to enhance this time interval beyond the coherence ...lifetime and thus gain precision. Here, we demonstrate that by using a quantum memory an increased sensitivity can also be achieved. To this end, we use entanglement in a hybrid spin system comprising a sensing and a memory qubit associated with a single nitrogen-vacancy centre in diamond. With the memory we retain the full quantum state even after coherence decay of the sensor, which enables coherent interaction with distinct weakly coupled nuclear spin qubits. We benchmark the performance of our hybrid quantum system against use of the sensing qubit alone by gradually increasing the entanglement of sensor and memory. We further apply this quantum sensor-memory pair for high-resolution NMR spectroscopy of single (13)C nuclear spins.
The bacterial flagellar type III export apparatus, which is required for flagellar assembly beyond the cell membranes, consists of a transmembrane export gate complex and a cytoplasmic ATPase ...complex. FlhA, FlhB, FliP, FliQ, and FliR form the gate complex inside the basal body MS ring, although FliO is required for efficient export gate formation in Salmonella enterica. However, it remains unknown how they form the gate complex. Here we report that FliP forms a homohexameric ring with a diameter of 10 nm. Alanine substitutions of conserved Phe-137, Phe-150, and Glu-178 residues in the periplasmic domain of FliP (FliPP) inhibited FliP6 ring formation, suppressing flagellar protein export. FliO formed a 5-nm ring structure with 3 clamp-like structures that bind to the FliP6 ring. The crystal structure of FliPP derived from Thermotoga maritia, and structure-based photo-crosslinking experiments revealed that Phe-150 and Ser-156 of FliPP are involved in the FliP-FliP interactions and that Phe-150, Arg-152, Ser-156, and Pro-158 are responsible for the FliP-FliO interactions. Overexpression of FliP restored motility of a ∆fliO mutant to the wild-type level, suggesting that the FliP6 ring is a functional unit in the export gate complex and that FliO is not part of the final gate structure. Copurification assays revealed that FlhA, FlhB, FliQ, and FliR are associated with the FliO/FliP complex. We propose that the assembly of the export gate complex begins with FliP6 ring formation with the help of the FliO scaffold, followed by FliQ, FliR, and FlhB and finally FlhA during MS ring formation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We employ a 77-81 GHz frequency-modulated continuous-wave (FMCW) millimeter-wave radar to sense anomalous vibrations during vehicle transport at highway speeds for the first time. Secure metallic ...containers can be breached during transport by means of drilling into their sidewalls but detecting a drilling signature is difficult because the large vibrations of transport drown out the small vibrations of drilling. For the first time, we demonstrate that it is possible to use a non-contact millimeter-wave radar sensor to detect this micron-scale intrusive drilling while highway-speed vehicle movement shakes the container. With the millimeter-wave radar monitoring the microdoppler signature of the container's vibrating walls, we create a novel signal-processing pipeline consisting of range-angle tracking, time-frequency analysis, horizontal stripe image convolution, and principal component analysis to create a robust and powerful detection statistic to alarm if drilling is present. To support this pipeline, we develop a statistical model combining the vibrating container and the random vibrations induced by vehicle movement to explore the robustness of the sensor's detection capabilities. The presented results strongly support the inclusion of a millimeter-wave radar vibration sensor into a transport security system.
Background
There has been limited research addressing the effects of constipation on work productivity and healthcare resource use.
Aims
To assess the effect of chronic constipation on health ...outcomes and healthcare resource use.
Methods
Using data from the 2007 National Health and Wellness Survey (NHWS), chronic constipation patients (
n
= 1,430) were propensity score-matched to controls (
n
= 1,430) on demographic and clinical characteristics. Differences between groups in health-related quality of life (SF-12v2), work productivity and activity impairment, and resource use in the last 6 months were examined. Mediation analyses were conducted in order to determine whether the relationship between constipation and resource use was caused by a reduction in health status.
Results
Chronic constipation patients reported significantly lower levels of health-related quality of life (physical component summary score: 39.57 vs. 43.73; mental component summary score: 43.19 vs. 47.86, all
P
-values < 0.01) and significantly higher levels of loss of work productivity and activity impairment (absenteeism: 9.08% vs. 5.20%; presenteeism: 29.52% vs. 19.09%; overall work impairment: 33.65% vs. 21.56%; activity impairment: 46.58% vs. 33.90%, all
P
-values < 0.01) compared to the matched controls. Chronic constipation patients also reported significantly more provider (7.73 vs. 5.63) and emergency room visits (0.52 vs. 0.30) in the past 6 months (all
P
-values < 0.01). Mediation analyses suggested that increased resource use among chronic constipation patients were partially a result of reduced health status.
Conclusions
Compared to matched controls, chronic constipation patients reported greater economic and humanistic burden. Alleviating the humanistic burden associated with constipation may have economic benefits.
Intubation and mechanical ventilation are common interventions performed in the emergency department (ED). These interventions cause pain and discomfort to patients and necessitate analgesia and ...sedation. Recent trends in the ED and intensive care unit focus on an analgesia-first model to improve patient outcomes. Initial data from our institution demonstrated an over-emphasis on sedation and an opportunity to improve analgesic administration. As a result of these findings, the ED undertook a quality improvement (QI) project aimed at improving analgesia administration and time to analgesia post-intubation.
We performed a pre-post study between January 2017-February 2019 in the ED. Patients over the age of 18 who were intubated using rapid sequence intubation (RSI) were included in the study. The primary outcome was the rate of analgesia administration; a secondary outcome was time to analgesia administration. Quality improvement interventions occurred in two phases: an initial intervention focused on nursing education only, and a subsequent intervention that included nursing and physician education.
During the study period, 460 patients were intubated in the ED and met inclusion/exclusion criteria. Prior to the first intervention, the average rate of analgesia administration was 57.3%; after the second intervention, the rate was 94.9% (P <0.01). Prior to the first intervention, average time to analgesia administration was 36.0 minutes; after the second intervention, the time was 16.6 minutes (P value <0.01).
This QI intervention demonstrates the ability of education interventions alone to increase the rate of analgesia administration and reduce the time to analgesia in post-intubation patients.
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