Neratinib and ado-trastuzumab emtansine for pretreated and untreated human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases: Translational Breast Cancer Research Consortium trial 022.

BACKGROUND: Treatment options for human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases (BCBMs) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab emtansine (T-DM1) when given in combination. In Translational Breast Cancer Research Consortium (TBCRC) 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. PATIENTS AND METHODS: In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts [cohort 4A-previously untreated BCBM, cohorts 4B and 4C-BCBM progressing after local CNS-directed therapy without (4B) and with (4C) prior exposure to T-DM1]. Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. The overall survival (OS) and toxicity were also assessed. RESULTS: Between 2018 and 2021, 6, 17, and 21 patients enrolled in cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% [95% confidence interval (CI) 4.3% to 77.7%], 35.3% (95% CI 14.2% to 61.7%), and 28.6% (95% CI 11.3% to 52.2%), respectively; 38.1%-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). The median OS was 30.2 [cohort 4A; 95% CI 21.9-not reached (NR)], 23.3 (cohort 4B; 95% CI 17.6-NR), and 20.9 (cohort 4C; 95% CI 14.9-NR) months. CONCLUSIONS: We observed intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pretreated.

"I'll meet you at our bench": adaptation, innovation and resilience among VCSE organisations who supported marginalised and minoritised communities during the Covid-19 pandemic in Northern England - a qualitative focus group study.

BACKGROUND: The Covid-19 pandemic has exacerbated pre-existing inequalities and increased adversity and challenges for vulnerable and marginalised communities worldwide. In the UK, the Voluntary Community and Social Enterprise (VCSE) sector play a vital role in supporting the health and wellbeing of people who are marginalised or experiencing multiple complex needs. However, only a small number of studies have focused on the impact that Covid-19 had on the VCSE sector. METHODS: As part of a Health Inequalities Impact Assessment (HIIA), we conducted qualitative focus groups with staff and volunteers from five organisations to examine short, medium and longer-term impacts of Covid-19 upon the VCSE sector in Northern England. Nine online focus groups were conducted between March and July 2021. FINDINGS: Focus group transcripts were analysed using Framework Analysis and yielded three central themes: (1) exacerbation of pre-existing inequalities, adversity and challenges for vulnerable and marginalised populations; (2) the 'price' of being flexible, innovative and agile for VCSE staff and volunteers; and (3) the voluntary sector as a 'lifeline' - organisational pride and resilience. CONCLUSIONS: While the voluntary sector 'adapted at pace' to provide support during Covid-19 and in its continued aftermath, this resilience has potentially come at the cost of workforce and volunteer wellbeing, compounded by political obstacles and chronic shortage in funding and support. The VCSE sector has a vital role to play in the post-lockdown 'levelling up' agenda. The expertise, capacity and resilience of VCSE organisations, and their ability to respond to Covid-19, should be celebrated, recognised and supported adequately to maintain its resilience. To not do so threatens the sector's sustainability and risks jeopardising attempts to involve the sector in addressing the social determinants of health.

Open-label, phase II, multicenter study of lasofoxifene plus abemaciclib for treating women with metastatic ER+/HER2- breast cancer and an ESR1 mutation after disease progression on prior therapies: ELAINE 2.

BACKGROUND: Acquired ESR1 mutations in estrogen receptor-positive (ER+) metastatic breast cancer (mBC) drive treatment resistance and tumor progression; new treatment strategies are needed. Lasofoxifene, a next-generation, oral, endocrine therapy and tissue-specific ER antagonist, provided preclinical antitumor activity, alone or combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in ESR1-mutated mBC. PATIENTS AND METHODS: In the open-label, phase II, ELAINE 2 trial (NCT04432454), women with ESR1-mutated, ER+/human epidermal growth factor receptor 2-negative (HER2-) mBC who progressed on prior therapies (including CDK4/6i) received lasofoxifene 5 mg/day and abemaciclib 150 mg b.i.d until disease progression/toxicity. The primary endpoint was safety/tolerability. Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), and objective response rate (ORR). RESULTS: Twenty-nine women (median age 60 years) participated; all but one were previously treated with a CDK4/6i (median duration 2 years). The lasofoxifene-abemaciclib combination was well tolerated with primarily grade 1/2 treatment-emergent adverse events (TEAEs), most commonly diarrhea, nausea, fatigue, and vomiting. One patient (with no prior CDK4/6i) discontinued treatment due to grade 2 diarrhea. No deaths occurred during the study. Median PFS was 56.0 weeks [95% confidence interval (CI) 31.9 weeks-not estimable; ∼13 months]; PFS rates at 6, 12, and 18 months were 76.1%, 56.1%, and 38.8%, respectively. CBR at 24 weeks was 65.5% (95% CI 47.3% to 80.1%). In 18 patients with measurable lesions, ORR was 55.6% (95% CI 33.7% to 75.4%). ESR1-mutant circulating tumor DNA (ctDNA) allele fraction decreased from baseline to week 4 in 21/26 (80.8%) patients. CONCLUSIONS: Lasofoxifene plus abemaciclib had an acceptable safety profile, was well tolerated, and exhibited meaningful antitumor activity in women with ESR1-mutated, ER+/HER2- mBC after disease progression on prior CDK4/6i. Observed decreases in ESR1-mutant ctDNA with lasofoxifene concordant with clinical response suggest target engagement. If the ELAINE 2 findings are confirmed in the initiated, phase III, ELAINE 3 trial, these data could be practice-changing and help address a critical unmet need.

Lytic to temperate switching of viral communities.

Microbial viruses can control host abundances via density-dependent lytic predator-prey dynamics. Less clear is how temperate viruses, which coexist and replicate with their host, influence microbial communities. Here we show that virus-like particles are relatively less abundant at high host densities. This suggests suppressed lysis where established models predict lytic dynamics are favoured. Meta-analysis of published viral and microbial densities showed that this trend was widespread in diverse ecosystems ranging from soil to freshwater to human lungs. Experimental manipulations showed viral densities more consistent with temperate than lytic life cycles at increasing microbial abundance. An analysis of 24 coral reef viromes showed a relative increase in the abundance of hallmark genes encoded by temperate viruses with increased microbial abundance. Based on these four lines of evidence, we propose the Piggyback-the-Winner model wherein temperate dynamics become increasingly important in ecosystems with high microbial densities; thus 'more microbes, fewer viruses'.

Mortality of various-age larval winter ticks, Dermacentor albipictus, following surface contact with entomopathogenic fungi.

The larval stage of the one-host tick, Dermacentor albipictus Packard (Acari: Ixodidae), the winter tick, is spent aggregated on the ground in summer until they quest for hosts in the autumn. Metarhizium brunneum (Petch) and Beauveria bassiana (Balsamo-Crivelli) Vuillemin are promising fungal biocontrol agents of ticks. The success of tick biocontrol using entomopathogenic fungi relies on infective propagule contact with a susceptible host at the right time within their life cycle and stage. The susceptibility of various-age D. albipictus larvae to commercial isolates of M. brunneum strain F52 (Mb-F52) and B. bassiana strain GHA (Bb-GHA) was assessed over a three-week period after contact with surfaces treated with 1.3 × 106 conidia/cm2. Larvae of four ages were examined (a) upon eclosion from eggs, (b) 2-weeks, (c) 1.5-months and (d) 3-months-old. Mortality of larvae exposed to fungus-treated surfaces ranged from 4 to 51% for Bb-GHA and 64-100% for Mb-F52 after three weeks. Significantly greater mortality was observed when larvae were exposed to Mb-F52 than Bb-GHA. Larval susceptibility was significantly greater within 2 weeks of eclosion from eggs and after 3 months of age. These results demonstrate the varying susceptibility of larvae to mycoacaricides at different times within their non-parasitic larval life stage.

Rapid detection of ciguatoxins in Gambierdiscus and Fukuyoa with immunosensing tools.

Consumption of seafood contaminated with ciguatoxins (CTXs) leads to a foodborne disease known as ciguatera. Primary producers of CTXs are epibenthic dinoflagellates of the genera Gambierdiscus and Fukuyoa. In this study, thirteen Gambierdiscus and Fukuyoa strains were cultured, harvested at exponential phase, and CTXs were extracted with an implemented rapid protocol. Microalgal extracts were obtained from pellets with a low cell abundance (20,000 cell/mL) and were then analyzed with magnetic bead (MB)-based immunosensing tools (colorimetric immunoassay and electrochemical immunosensor). It is the first time that these approaches are used to screen Gambierdiscus and Fukuyoa strains, providing not only a global indication of the presence of CTXs, but also the ability to discriminate between two series of congeners (CTX1B and CTX3C). Analysis of the microalgal extracts revealed the presence of CTXs in 11 out of 13 strains and provided new information about Gambierdiscus and Fukuyoa toxin profiles. The use of immunosensing tools in the analysis of microalgal extracts facilitates the elucidation of further knowledge regarding these dinoflagellate genera and can contribute to improved ciguatera risk assessment and management.

Constraining the Neutron Star Compactness: Extraction of the

The ^{23}Al(p,γ)^{24}Si reaction is among the most important reactions driving the energy generation in type-I x-ray bursts. However, the present reaction-rate uncertainty limits constraints on neutron star properties that can be achieved with burst model-observation comparisons. Here, we present a novel technique for constraining this important reaction by combining the GRETINA array with the neutron detector LENDA coupled to the S800 spectrograph at the National Superconducting Cyclotron Laboratory. The ^{23}Al(d,n) reaction was used to populate the astrophysically important states in ^{24}Si. This enables a measurement in complete kinematics for extracting all relevant inputs necessary to calculate the reaction rate. For the first time, a predicted close-lying doublet of a 2_{2}^{+} and (4_{1}^{+},0_{2}^{+}) state in ^{24}Si was disentangled, finally resolving conflicting results from two previous measurements. Moreover, it was possible to extract spectroscopic factors using GRETINA and LENDA simultaneously. This new technique may be used to constrain other important reaction rates for various astrophysical scenarios.

Dynamic imaging with sialography combined with sialendoscopy to manage a foreign body in Stensen's duct.

OBJECTIVE: We describe sialography as a dynamic imaging modality useful in establishing the diagnosis and planning for treatment of a parotid gland ductal foreign body. METHODS: Chart and radiographic imaging review of a 75 year-old male who had obstructive sialadenitis symptoms two years after welding slag pierced the cheek skin and identified as a 'piece of steel stuck in his cheek'. RESULTS: Sialography was used to demonstrate a foreign body adjacent to the parotid gland to indicate its presence as a mobile element within the ductal system associated with marked pre-obstructive duct dilation. Sialendoscopy was used to successfully remove the foreign body. CONCLUSIONS: In selected cases, the management of obstructive sialadenitis can be improved with sialography in permitting dynamic imaging of salivary duct anatomy. Although ultrasound has evolved as a standard component of salivary gland assessment, sialography may complement imaging with ultrasound (or CT as in this case) to offer the highest acuity definition of the salivary ducts.

Observation of the Isovector Giant Monopole Resonance via the

The (^{10}Be,^{10}B^{*}[1.74 MeV]) charge-exchange reaction at 100 AMeV is presented as a new probe for isolating the isovector (ΔT=1) nonspin-transfer (ΔS=0) response of nuclei, with ^{28}Si being the first nucleus studied. By using a secondary ^{10}Be beam produced by fast fragmentation of ^{18}O nuclei at the NSCL Coupled Cyclotron Facility, applying the dispersion-matching technique with the S800 magnetic spectrometer to determine the excitation energy in ^{28}Al, and performing high-resolution γ-ray tracking with the Gamma-Ray Energy Tracking In-beam Nuclear Array (GRETINA) to identify the 1022-keV γ ray associated with the decay from the 1.74-MeV T=1 isobaric analog state in ^{10}B, a ΔS=0 excitation-energy spectrum in ^{28}Al was extracted. Monopole and dipole contributions were determined through a multipole-decomposition analysis, and the isovector giant dipole resonance and isovector giant monopole resonance (IVGMR) were identified. The results show that this probe is a powerful tool for studying the elusive IVGMR, which is of interest for performing stringent tests of modern density functional theories at high excitation energies and for constraining the bulk properties of nuclei and nuclear matter. The extracted distributions were compared with theoretical calculations based on the normal-modes formalism and the proton-neutron relativistic time-blocking approximation. Calculated cross sections based on these strengths underestimate the data by about a factor of 2, which likely indicates deficiencies in the reaction calculations based on the distorted wave Born approximation.

Estimating sleep time from non-EEG-based PSG signals in the diagnosis of sleep-disordered breathing.

PURPOSE: The purpose of this study was to use non-EEG PSG signals to estimate TST in order to diagnose SDB with a greater sensitivity than type 3 device methodology that relies on TRT. METHODS: Movement patterns were obtained from the thoracoabdominal signals of adult PSG recordings (n = 60) in the laboratory and the home. Parameters obtained allowed, with 95% certainty, identification of sleep and wake based on the duration of movements and quiescent time (Qd). Snoring, apneas, and hypopneas indicated sleep with 100% certainty. The method was tested in a different set of PSG recordings (n = 80). RESULTS: Subjects lay awake and immobile for longer in the laboratory (QdLAB = 27.4 (12.1, 62.0), QdHOME = 16.0 s (8.0, 36.0); p < 0.0001) but asleep and immobile for longer at home (QdLAB = 65.2 (23.0, 121.4), QdHOME = 95.0 s (44.5, 247.5); 0.005). Only 5% of wake Qd periods were >173 s in the laboratory and >105 s at home. In both locations, 95% of movements during sleep were <10 s. Experimental TST values were 21 min shorter than EEG-defined TST and, combined with fewer scored respiratory events, produced AHI values that were 1.6 events/h lower than the reference. The experimental TST increased the sensitivity of SDB diagnosis from 73 to 97%. CONCLUSIONS: In the sleep laboratory, subjects are immobile for longer periods when awake and for shorter periods when asleep. The experimental TST was similar to EEG-defined TST and could be used to diagnose SDB with a much higher sensitivity than the type 3 method.

Assessing the delivery of alcohol screening and brief intervention in sexual health clinics in the north east of England.

BACKGROUND: Risky drinking is associated with risky sexual experiences, however the relationship between alcohol and sex is complex. The aim of the study was to assess the feasibility of delivering alcohol screening and brief interventions in genitourinary medicine (GUM) clinics. The objectives were to; understand the levels of alcohol use amongst patients; report on the number of alcohol interventions delivered; and to analyse the relationship between alcohol use with demographic data as well as diagnosed sexually transmitted infections (STIs) to see if there were any associations. METHODS: All new patients attending GUM between April 2012 and March 2013 self-completed the Alcohol Use Disorder Identification Test (AUDIT) prior to their clinical consultation. Where appropriate (scoring 8+ on AUDIT) the clinician would deliver up to 2-3 min of alcohol brief intervention. Descriptive statistics, t-tests, ANOVA and logistic regression were carried out as appropriate. RESULTS: AUDIT scores were available for 90% of all new patients (3058/3390) with an average mean score of 7.75. Of those who drank alcohol, 44% were categorised as being AUDIT positive, including 2% who had a score indicative of probable alcohol dependence (20+). 55 % (n = 638) of patients who screened positive on the AUDIT received a brief intervention whilst 24% (n = 674) of drinkers were diagnosed with a STI. Logistic regression modelling revealed that males, younger age groups and those of 'white' ethnicity were more likely to score positive on AUDIT. Patients classified as non-students, living in deprivation quintiles one to four and categorised as probable alcohol dependence on the AUDIT were more likely to be diagnosed with an STI. CONCLUSION: It is possible to embed alcohol screening into routine practice within sexual health services however further work is required to embed brief interventions particularly amongst increasing risk drinkers. If resources are limited, services may consider more targeted rather than universal alcohol screening to specific population groups. The study was undertaken in one GUM service in the North East of England and therefore findings may not be generalizable. The study did not assess efficacy of alcohol brief intervention in this setting.

Re-aerosolization of Bacillus thuringiensis spores from concrete and turf.

Spores of Bacillus anthracis deposited on surfaces can become airborne again as a result of air currents and mechanical forces. As such, they are a potential source of infection by inhalation. Spores of Bacillus thuringiensis were used to quantify this phenomenon in a simulation of outdoor conditions. Concrete and turf surfaces were inoculated by aerosol to produce high spore densities (greater than 1 × 109  CFU per m2 ) which were then subjected to the passage of air at 10 ms-1 with and without simulated walking. Re-aerosolized spores were sampled by wetted wall cyclone air samplers. The mean total re-aerosolization rate from concrete (m-2  min-1 ) was 1·16 × 10-3 for wind alone and 3·2 × 10-3 for wind and simulated walking while for turf the respective values were 2·7 × 10-4 and 6·7 × 10-4 . SIGNIFICANCE AND IMPACT OF THE STUDY: Following the malicious and/or accidental release of an aerosol of Bacillus anthracis spores, the immediate risk of human inhalation would decrease as the spores were deposited on surfaces or diluted by wind flow. There is, however, a concern that the deposited spores could become re-aerosolized and so present an ongoing hazard. Using an accurate simulant for B. anthracis spores a method is reported here that allowed the enumeration of re-aerosolized spores from concrete and turf by wind flow and footfall. Under the conditions used, the rates of re-aerosolization were low. These findings will need to be verified under real outdoor conditions before the true significance in terms of secondary exposure to pathogenic spores can be assessed.

Elevated carbon dioxide has limited acute effects on Lepomis macrochirus behaviour.

The current study investigated the behavioural response of Lepomis macrochirus following exposures to elevated carbon dioxide (CO2 ). For this, L. macrochirus were held at ambient pCO2 (160 µatm pCO2 ) for 7 days, then exposed to elevated pCO2 (8300 µatm pCO2 ) for 5 days, and then returned to ambient conditions for a further 5 days to recover. At the end of each exposure period, several behavioural metrics were quantified (boldness, lateralization and activity). Data showed no change in lateralization and most metrics associated with performance and boldness. During the boldness test, however, average velocity, velocity in the thigmotaxis (outer) zone and proportion of activity in the thigmotaxis zone increased with pCO2 exposure. During post-exposure, average velocity of L. macrochirus decreased. In addition, individual rank was repeatable during the pre-exposure and post-exposure period in three of the 17 metrics investigated (average velocity in the middle zone, average velocity near object and total shuttles to the object zone), but not during the CO2 exposure period, suggesting that elevated pCO2 disrupted some behavioural performances. Overall, this study found elevated pCO2 caused disruption to behaviours of freshwater fishes such as L. macrochirus and effects do not appear to be as serious as has been shown for marine fishes.

The Relationship Between Verified Organ Donor Designation and Patient Demographic and Medical Characteristics.

Previous studies on the correlates of organ donation consent have focused on self-reported willingness to donate and on self-reported medical suitability to donate. However, these may be subject to social desirability bias and inaccurate assessments of medical suitability. The authors sought to overcome these limitations by directly verifying donor designation on driver's licenses and by abstracting comorbid conditions from electronic health records. Using a cross-sectional study design, they reviewed the health records of 2070 randomly selected primary care patients at a large urban safety-net medical system to obtain demographic and medical characteristics. They also examined driver's licenses that were scanned into electronic health records as part of the patient registration process for donor designation. Overall, 943 (46%) patients were designated as a donor on their driver's license. On multivariate analysis, donor designation was positively associated with age 35-54 years, female sex, nonblack race, speaking English or Spanish, being employed, having private insurance, having an income >$45 000, and having fewer comorbid conditions. These demographic and medical characteristics resulted in patient subgroups with donor designation rates ranging from 21% to 75%. In conclusion, patient characteristics are strongly related to verified donor designation. Further work should tailor organ donation efforts to specific subgroups.

ANG1005 for breast cancer brain metastases: correlation between 18F-FLT-PET after first cycle and MRI in response assessment.

PURPOSE: Improved therapies and imaging modalities are needed for the treatment of breast cancer brain metastases (BCBM). ANG1005 is a drug conjugate consisting of paclitaxel covalently linked to Angiopep-2, designed to cross the blood-brain barrier. We conducted a biomarker substudy to evaluate 18F-FLT-PET for response assessment. METHODS: Ten patients with measurable BCBM received ANG1005 at a dose of 550 mg/m2 IV every 21 days. Before and after cycle 1, patients underwent PET imaging with 18F-FLT, a thymidine analog, retention of which reflects cellular proliferation, for comparison with gadolinium-contrast magnetic resonance imaging (Gd-MRI) in brain metastases detection and response assessment. A 20 % change in uptake after one cycle of ANG1005 was deemed significant. RESULTS: Thirty-two target and twenty non-target metastatic brain lesions were analyzed. The median tumor reduction by MRI after cycle 1 was -17.5 % (n = 10 patients, lower, upper quartiles: -25.5, -4.8 %) in target lesion size compared with baseline. Fifteen of twenty-nine target lesions (52 %) and 12/20 nontarget lesions (60 %) showed a ≥20 % decrease post-therapy in FLT-PET SUV change (odds ratio 0.71, 95 % CI: 0.19, 2.61). The median percentage change in SUVmax was -20.9 % (n = 29 lesions; lower, upper quartiles: -42.4, 2.0 %), and the median percentage change in SUV80 was also -20.9 % (n = 29; lower, upper quartiles: -49.0, 0.0 %). Two patients had confirmed partial responses by PET and MRI lasting 6 and 18 cycles, respectively. Seven patients had stable disease, receiving a median of six cycles. CONCLUSIONS: ANG1005 warrants further study in BCBM. Results demonstrated a moderately strong association between MRI and 18F-FLT-PET imaging.

Global threats to human water security and river biodiversity.

Protecting the world's freshwater resources requires diagnosing threats over a broad range of scales, from global to local. Here we present the first worldwide synthesis to jointly consider human and biodiversity perspectives on water security using a spatial framework that quantifies multiple stressors and accounts for downstream impacts. We find that nearly 80% of the world's population is exposed to high levels of threat to water security. Massive investment in water technology enables rich nations to offset high stressor levels without remedying their underlying causes, whereas less wealthy nations remain vulnerable. A similar lack of precautionary investment jeopardizes biodiversity, with habitats associated with 65% of continental discharge classified as moderately to highly threatened. The cumulative threat framework offers a tool for prioritizing policy and management responses to this crisis, and underscores the necessity of limiting threats at their source instead of through costly remediation of symptoms in order to assure global water security for both humans and freshwater biodiversity.

The lived experience of fatigue in children and adolescents with cancer: a systematic review.

PURPOSE: Objectives of this systematic review were to summarize how fatigue has been described from the perspective of children and adolescents with cancer, the impact of fatigue on quality of life, and child reported contributing factors and potential alleviators of fatigue. METHODS: We conducted electronic searches of Ovid Medline, EMBASE, PsycInfo, Science Citation, Social Science Citation (Web of Science), and CINAHL. We included studies of children and adolescents with cancer in which the experience of fatigue was described by the child/adolescent. The search was restricted to publications in English. Themes were summarized. RESULTS: Eleven studies were represented in 18 publications. Ages of included children ranged from 6 to 19 years. Majority of studies used semi-structured interviews to elicit participant's perceptions of fatigue. Terms used to describe fatigue included the following: tiredness, weary, loss of strength, dizziness, feeling drained, feeling drowsy, lacking motivation, exhaustion, and feeling emotional. Impact of fatigue related to not being able to participate in regular activities; needing to sleep or rest more; and impact on psychosocial health. Perceived alleviators of fatigue included exercise, distraction, rest, eating, and drinking. CONCLUSIONS: Fatigue is impactful from the perspective of children and adolescents. Future research should focus on prospective exploration of the impact of fatigue on pediatric cancer patients and identifying approaches to reduce fatigue.

Patient characteristics, interventions and outcomes of 1151 rapid response team activations in a tertiary hospital: a prospective study.

BACKGROUND: The characteristics of mature contemporary rapid response systems are unclear. AIM: To determine the patient characteristics, processes and outcomes, both in-hospital and post-discharge, of a well-established rapid response system in a tertiary adult hospital. METHODS: This is a prospective study of consecutive rapid response team (RRT) activations between 1 July and 25 November 2015. Variables included patient characteristics, timing, location and triggers of RRT activations, interventions undertaken, mortality and readmission status at 28 days post-discharge. RESULTS: A total of 1151 RRT activations was analysed (69.1 per 1000 admissions), involving 800 patients, of whom 81.5% were emergency admissions. A total of 351 (30.5%) activations comprised repeat activations for the same patient. Most activations (723; 62.8%) occurred out of hours, and 495 (43%) occurred within 48 h of admission. Hypotension, decreased level of consciousness and oxygen desaturation were the most common triggers. Advanced life support was undertaken in less than 7%; 198 (17.2%) responses led to transfer to higher-level care units. Acute resuscitation plans were noted for only 29.1% of RRT activations, with 80.3% stipulating supportive care only. A total of 103 (12.6%) patients died in hospital, equalling 14 deaths per 100 RRT activations. At 28 days, 150 (18.8%) patients had died, significantly more among those with multiple versus single RRT activations (24.9 vs 16.6%; odds ratio 1.66, 95% confidence interval 1.31-2.44; P = 0.013). CONCLUSION: Relatively few RRT activations are associated with acute resuscitation plans, and most interventions during RRT responses are low level. The high rate of post-RRT deaths and transfers to higher-level care units calls for the prospective identification of such patients in targeting appropriate care.

Neutralization of mitochondrial superoxide by superoxide dismutase 2 promotes bacterial clearance and regulates phagocyte numbers in zebrafish.

Mitochondria are known primarily as the location of the electron transport chain and energy production in cells. More recently, mitochondria have been shown to be signaling centers for apoptosis and inflammation. Reactive oxygen species (ROS) generated as by-products of the electron transport chain within mitochondria significantly impact cellular signaling pathways. Because of the toxic nature of ROS, mitochondria possess an antioxidant enzyme, superoxide dismutase 2 (SOD2), to neutralize ROS. If mitochondrial antioxidant enzymes are overwhelmed during severe infections, mitochondrial dysfunction can occur and lead to multiorgan failure or death. Pseudomonas aeruginosa is an opportunistic pathogen that can infect immunocompromised patients. Infochemicals and exotoxins associated with P. aeruginosa are capable of causing mitochondrial dysfunction. In this work, we describe the roles of SOD2 and mitochondrial ROS regulation in the zebrafish innate immune response to P. aeruginosa infection. sod2 is upregulated in mammalian macrophages and neutrophils in response to lipopolysaccharide in vitro, and sod2 knockdown in zebrafish results in an increased bacterial burden. Further investigation revealed that phagocyte numbers are compromised in Sod2-deficient zebrafish. Addition of the mitochondrion-targeted ROS-scavenging chemical MitoTEMPO rescues neutrophil numbers and reduces the bacterial burden in Sod2-deficient zebrafish. Our work highlights the importance of mitochondrial ROS regulation by SOD2 in the context of innate immunity and supports the use of mitochondrion-targeted ROS scavengers as potential adjuvant therapies during severe infections.