Human eosinophil-airway smooth muscle cell interactions.

Eosinophils are present throughout the airway wall of asthmatics. The nature of the interaction between human airway smooth muscle cells (ASMC) and eosinophils was investigated in this study. We demonstrated, using light microscopy, that freshly isolated eosinophils from healthy donors rapidly attach to ASMC in vitro. Numbers of attached eosinophils were highest at 2 h, falling to 50% of maximum by 20 h. Eosinophil attachment at 2 h was reduced to 72% of control by anti-VCAM-1, and to 74% at 20 h by anti-ICAM-1. Pre-treatment of ASMC for 24h with TNF-alpha, 10 nM, significantly increased eosinophil adhesion to 149 and 157% of control after 2 and 20 h. These results provide evidence that eosinophil interactions with ASMC involve VCAM-1 and ICAM-1 and are modulated by TNF-alpha

Timing of Contact X-ray Brachytherapy in organ-preserving treatment of rectal cancer

Timing of Contact X-ray Brachytherapy in organ-preserving treatment of small rectal cancer Objective For patients with early rectal cancer, who are either at high risk for or refuse surgery, a planned organ preservation treatment involving a combination of external beam radiotherapy (EBRT) and Contact X-ray Brachytherapy (CXB) can be offered as an alternative option to surgery. (1-3) However, the ideal sequence of treatment for small rectal tumours (≤3cm), whether to administer CXB first or after EBRT, has not yet been well established, leading to variable sequences of this organ-preserving treatment being used.(3-5) This study has compared the oncological outcomes between the two treatment approaches using propensity score matching and inverse probability treatment weighting (IPTW) analysis to evaluate whether starting with CXB confers any benefits to patients. Method We analysed patients who had undergone both EBRT and CXB with curative intent, regardless of the treatment sequence, from the prospectively collected database at Clatterbridge Cancer Centre (2008-2019). Only patients who had well to moderately differentiated rectal adenocarcinoma (cT1-3, cN0-1, cM0) and small tumour size (≤ 3cm) were included. The variables of age, sex, fitness for surgery, performance status, tumour stage, nodal stage, EBRT regimen and CXB total dose, were considered possible confounders of the association between treatment regimen and outcomes. The balance of covariates before and after propensity matching and IPTW was assessed by examining the standardised mean difference (SMD) between the groups (Figure 1). The oncological outcomes based on the treatment sequence were first assessed in an unadjusted analysis followed by an adjusted model analysis considering all variables as confounders. Then, we performed propensity score matching (nearest-neighbour method, calliper= 0.25) and calculated IPTW to weigh the full cohort in each regression model. Statistical analysis was performed in R 4.3.1. The primary outcome measures were overall survival (OS) and disease-free survival (DFS). Secondary outcome measures consisted of the local regrowth rate, organ preservation rate, and presence of post-treatment rectal bleeding. Results A total of 251 eligible patients, who received either EBRT (n=103) or CXB (n=148) as their initial treatment with curative intent were included in the study. Patients received a CXB dose of 90-110Gy in 3-4 fractions over 4-6 weeks (each fraction two weeks apart) either before or after EBRT. EBRT was administered either as long-course chemoradiotherapy (45-50Gy/25 #/35 days), long-course radiotherapy alone (45Gy/20#/28days), or short-course radiotherapy (25Gy/5#/5 days). Following treatment, a watch-and-wait policy was adopted for patients who achieved a clinical complete/near response. The median follow-up was 37 [IQR:18-56] months for the EBRT-first group and 32 [IQR:16-54] months for the CXB-first group. In the unadjusted analysis, a higher risk of grade-1(26%) and grade-2(6%) rectal bleeding (p=0.008) was observed in patients who started with CXB, but no significant differences in any of the survival parameters were found. Analysis using the adjusted, propensity matching, and IPTW models, demonstrated a significant improvement of OS (p=0.04, HR (95%CI): 0.69 (0.48-0.98) and a higher risk of grade 1-2 rectal bleeding (p=0.01, OR (95%CI): 2.35(1.16-4.76) in those patients who had been received CXB as their initial treatment (Figure 2). However, DFS (p=0.87), local regrowth rate (p=0.70), and organ preservation rate (p=0.80) were not significantly different between the two groups. Conclusion Small rectal cancer (≤3cm), commencing treatment with CXB, as opposed to EBRT, was associated with improved overall survival, despite an increased risk of grade 1 and 2 rectal bleeding. However, there was no statistically significant improvement in terms of disease-free survival, local regrowth rate, or organ preservation rate with this treatment strategy

Clinical prediction models assessing response to radiotherapy for rectal cancer: protocol for a systematic review.

BackgroundRectal cancer has a high prevalence. The standard of care for management of localised disease involves major surgery and/or chemoradiotherapy, but these modalities are sometimes associated with mortality and morbidity. The notion of 'watch and wait' has therefore emerged and offers an organ-sparing approach to patients after administering a less invasive initial treatment, such as X-ray brachytherapy (Papillon technique). It is thus important to evaluate how likely patients are to respond to such therapies, to develop patient-tailored treatment pathways. We propose a systematic review to identify published clinical prediction models of the response of rectal cancer to treatment that includes radiotherapy and here present our protocol.MethodsIncluded studies will develop multivariable clinical prediction models which assess response to treatment and overall survival of adult patients who have been diagnosed with any stage of rectal cancer and have received radiotherapy treatment with curative intent. Cohort studies and randomised controlled trials will be included. The primary outcome will be the occurrence of salvage surgery at 1 year after treatment. Secondary outcomes include salavage surgery at at any reported time point, the predictive accuracy of models, the quality of the developed models and the feasibility of using the model in clinical practice. Ovid MEDLINE, PubMed, Cochrane Library, EMBASE and CINAHL will be searched from inception to 24 February 2022. Keywords and phrases related to rectal cancer, radiotherapy and prediction models will be used. Studies will be selected once the deduplication, title, abstract and full-text screening process have been completed by two independent reviewers. The PRISMA-P checklist will be followed. A third reviewer will resolve any disagreement. The data extraction form will be pilot-tested using a representative 5% sample of the studies reviewed. The CHARMS checklist will be implemented. Risk of bias in each study will be assessed using the PROBAST tool. A narrative synthesis will be performed and if sufficient data are identified, meta-analysis will be undertaken as described in Debray et al. DISCUSSION: This systematic review will identify factors that predict response to the treatment protocol. Any gaps for potential development of new clinical prediction models will be highlighted.Trial registrationCRD42022277704

Evaluation of a community pharmacy-based intervention for improving patient adherence to antihypertensives: a randomised controlled trial

BackgroundThe majority of patients using antihypertensive medications fail to achieve their recommended target blood pressure. Poor daily adherence with medication regimens and a lack of persistence with medication use are two of the major reasons for failure to reach target blood pressure. There is no single intervention to improve adherence with antihypertensives that is consistently effective. Community pharmacists are in an ideal position to promote adherence to chronic medications. This study aims to test a specific intervention package that could be integrated into the community pharmacy workflow to enable pharmacists to improve patient adherence and/or persistence with antihypertensive medications - Hypertension Adherence Program in Pharmacy (HAPPY).Methods/DesignThe HAPPY trial is a multi-centre prospective randomised controlled trial. Fifty-six pharmacies have been recruited from three Australian states. To identify potential patients, a software application (MedeMine CVD) extracted data from a community pharmacy dispensing software system (FRED Dispense&reg;). The pharmacies have been randomised to either \u27Pharmacist Care Group\u27 (PCG) or \u27Usual Care Group\u27 (UCG). To check for \u27Hawthorne effect\u27 in the UCG, a third group of patients \u27Hidden Control Group\u27 (HCG) will be identified in the UCG pharmacies, which will be made known to the pharmacists at the end of six months. Each study group requires 182 patients. Data will be collected at baseline, three and six months in the PCG and at baseline and six months in the UCG. Changes in patient adherence and persistence at the end of six months will be measured using the self-reported Morisky score, the Tool for Adherence Behaviour Screening and medication refill data.DiscussionTo our knowledge, this is the first research testing a comprehensive package of evidence-based interventions that could be integrated into the community pharmacy workflow to enable pharmacists to improve patient adherence and/or persistence with antihypertensive medications. The unique features of the HAPPY trial include the use of MedeMine CVD to identify patients who could potentially benefit from the service, control for the \u27Hawthorne effect\u27 in the UCG and the offer of the intervention package at the end of six months to patients in the UCG, a strategy that is expected to improve retention.Trial RegistrationAustralian New Zealand Clinical Trial Registry ACTRN12609000705280<br /

Contact X-ray brachytherapy (CXB) as a salvage treatment for rectal cancer patients who developed local tumor re-growth after watch-and-wait approach.

PurposeA watch-and-wait approach is an alternative to surgery for rectal cancer patients who have achieved a clinical complete response (cCR) following neoadjuvant (chemo)radiotherapy. However, approximately 25-38% of patients experience subsequent local tumor re-growth that requires salvage surgery. We evaluated the effectiveness of contact X-ray brachytherapy (CXB) as an alternative method of salvage therapy for those patients who were either unfit for or refused surgery. Oncological outcomes, tolerability, and feasibility of subsequent surgery for local treatment failure following CXB were reported.Material and methodsFrom 2009-2021, all patients treated with CXB as salvage therapy for local rectal cancer re-growth after watch-and-wait approach at our center were analyzed.ResultsContact X-ray brachytherapy as a salvage treatment (range, 90-110 Gy) was offered to 56 patients who experienced tumor re-growth following (chemo)radiation and watch-and-wait protocol. Median age was 76 (IQR = 66-83) years. Most patients (82%) had early-stage re-growth (ycT1/ycT2, ycN0), and 18% had more advanced stages (ycT3/ycT4, ycN0). After a median of 37-month follow-up (IQR = 19-53), 48% of patients who had early-stage re-growth achieved a sustained complete remission after CXB compared with 20% of those who had more advanced tumor stages. Disease-free and overall survivals for the whole cohort were 69% and 100% at 1-year, 51% and 82% at 3-year, and 51% and 65% at 5-years. CXB effectively controlled local re-growth-related symptoms. Mild post-CXB side effects occurred in 18% of cases. All (100%) eight patients who developed further local relapse, and 29% of those who had residual disease post-CXB salvage were successfully managed with subsequent surgery.ConclusionsContact X-ray brachytherapy offers a new treatment option for patients in this situation whose other therapy options are not suitable for or refused initial surgery. Early local tumor re-growth responded best with minimal treatment-related toxicity and excellent symptom control. Disease-free and overall survival rates were acceptable, and delaying surgical salvage for local re-growth did not compromise patients' eventual long-term outcomes

The Atacama Cosmology Telescope: Temperature and Gravitational Lensing Power Spectrum Measurements from Three Seasons of Data

We present the temperature power spectra of the cosmic microwave background (CMB) derived from the three seasons of data from the Atacama Cosmology Telescope (ACT) at 148 GHz and 218 GHz, as well as the cross-frequency spectrum between the two channels. We detect and correct for contamination due to the Galactic cirrus in our equatorial maps. We present the results of a number of tests for possible systematic error and conclude that any effects are not significant compared to the statistical errors we quote. Where they overlap, we cross-correlate the ACT and the South Pole Telescope (SPT) maps and show they are consistent. The measurements of higher-order peaks in the CMB power spectrum provide an additional test of the Lambda CDM cosmological model, and help constrain extensions beyond the standard model. The small angular scale power spectrum also provides constraining power on the Sunyaev-Zel'dovich effects and extragalactic foregrounds. We also present a measurement of the CMB gravitational lensing convergence power spectrum at 4.6-sigma detection significance.Comment: 21 pages; 20 figures, Submitted to JCAP, some typos correcte

The Atacama Cosmology Telescope: Two-Season ACTPol Lensing Power Spectrum

We report a measurement of the power spectrum of cosmic microwave background (CMB) lensing from two seasons of Atacama Cosmology Telescope Polarimeter (ACTPol) CMB data. The CMB lensing power spectrum is extracted from both temperature and polarization data using quadratic estimators. We obtain results that are consistent with the expectation from the best-fit Planck LCDM model over a range of multipoles L=80-2100, with an amplitude of lensing A_lens = 1.06 +/- 0.15 (stat.) +/- 0.06 (sys.) relative to Planck. Our measurement of the CMB lensing power spectrum gives sigma_8 Omega_m^0.25 = 0.643 +/- 0.054; including baryon acoustic oscillation scale data, we constrain the amplitude of density fluctuations to be sigma_8 = 0.831 +/- 0.053. We also update constraints on the neutrino mass sum. We verify our lensing measurement with a number of null tests and systematic checks, finding no evidence of significant systematic errors. This measurement relies on a small fraction of the ACTPol data already taken; more precise lensing results can therefore be expected from the full ACTPol dataset.Comment: 17 pages, 11 figures, to be submitted to Physical Review

Exploiting solid-state dynamic nuclear polarization NMR spectroscopy to establish the spatial distribution of polymorphic phases in a solid material

Solid-state DNP NMR can enhance the ability to detect minor amounts of solid phases within heterogenous materials. Here we demonstrate that NMR contrast based on transport of DNP-enhanced polarization can be exploited in the challenging case of early detection of a small amount of a minor polymorphic phase within a major polymorph, and we show that this approach can yield quantitative information on the spatial distribution of the two polymorphs. We focus on the detection of a minor amount (<4%) of polymorph III of m-aminobenzoic acid within a powder sample of polymorph I at natural isotopic abundance. Based on proposed models of the spatial distribution of the two polymorphs, simulations of 1H spin diffusion allow NMR data to be calculated for each model as a function of particle size and the relative amounts of the polymorphs. Comparison between simulated and experimental NMR data allows the model(s) best representing the spatial distribution of the polymorphs in the system to be established

Detection of the Power Spectrum of Cosmic Microwave Background Lensing by the Atacama Cosmology Telescope

We report the first detection of the gravitational lensing of the cosmic microwave background through a measurement of the four-point correlation function in the temperature maps made by the Atacama Cosmology Telescope. We verify our detection by calculating the levels of potential contaminants and performing a number of null tests. The resulting convergence power spectrum at 2-degree angular scales measures the amplitude of matter density fluctuations on comoving length scales of around 100 Mpc at redshifts around 0.5 to 3. The measured amplitude of the signal agrees with Lambda Cold Dark Matter cosmology predictions. Since the amplitude of the convergence power spectrum scales as the square of the amplitude of the density fluctuations, the 4-sigma detection of the lensing signal measures the amplitude of density fluctuations to 12%.Comment: 4 pages, 4 figures, replaced title and author list with version accepted by Physical Review Letters. Likelihood code can be downloaded from http://bccp.lbl.gov/~sudeep/ACTLensLike.htm