White matter lesions and the risk of incident hip fracture in older persons: results from the progetto veneto anziani study.

BACKGROUND: White matter lesions (WMLs) are associated with hypertension, an increased risk of falling, and impaired physical and cognitive performance that may affect the mechanical effect of falls. METHODS: We hypothesized that WMLs are a risk factor for hip fracture (HF). We studied a sample of 820 community-dwelling Italian persons 65 years and older from the cohort of the Progetto Veneto Anziani Study who underwent brain magnetic resonance imaging at baseline. Subjects were classified as having no lesions, focal lesions, or diffuse WMLs. RESULTS: Compared with those with no lesions, participants with diffuse WMLs were older, reported more falls, and had worse physical and cognitive performance, all factors implicated in the causal pathway to HF. During 9 years of follow-up, 51 HFs occurred. Hip fracture risk associated with diffuse WMLs markedly differed between participants younger than 80 years vs those 80 years and older. After adjustment among participants younger than 80 years, diffuse WMLs compared with no lesions were associated with a 2.7-fold (95% confidence interval, 1.1-7.1) increase in the risk of HF. Focal lesions were not statistically significantly associated with an increased risk of HF in the same age group (hazard ratio, 2.0; 95% confidence interval, 0.6-7.6). No associations between diffuse WMLs, focal lesions, and HF were evident among participants 80 years and older, possibly because of the limited sample size. CONCLUSIONS: White matter lesions represent an independent risk factor for HF in persons younger than 80 years. Older persons with diffuse WMLs should be considered candidates for multifactorial interventions aimed at reducing the risk of falling and fractures

Tarikh lihat anak bulan Syawal 25 April

Background: The GRPR-antagonist-based radioligands [67/68Ga/111In/177Lu]NeoBOMB1 have shown excellent theragnostic profiles in preclinical prostate cancer models, while [68Ga]NeoBOMB1 effectively visualized prostate cancer lesions in patients. We were further interested to explore the theragnostic potential of NeoBOMB1 in GRPR-positive mammary carcinoma, by first studying [67Ga]NeoBOMB1 in breast cancer models; Methods: We investigated the profile of [67Ga]NeoBOMB1, a [68Ga]NeoBOMB1 surrogate, in GRPR-expressing T-47D cells and animal models; Results: NeoBOMB1 (IC50s of 2.2 ± 0.2 nM) and [natGa]NeoBOMB1 (IC50s of 2.5 ± 0.2 nM) exhibited high affinity for the GRPR. At 37◦C [67Ga]NeoBOMB1 strongly bound to the T-47D cell-membrane (45.8 ± 0.4% at 2 h), internalizing poorly, as was expected for a radioantagonist. [67Ga]NeoBOMB1 was detected >90% intact in peripheral mouse blood at 30 min pi. In mice bearing T-47D xenografts, [67Ga]NeoBOMB1 specifically localized in the tumor (8.68 ± 2.9% ID/g vs. 0.6 ± 0.1% ID/g during GRPR-blockade at 4 h pi). The unfavorably high pancreatic uptake could be considerably reduced (206.29 ± 17.35% ID/g to 42.46 ± 1.31% ID/g at 4 h pi) by increasing the NeoBOMB1 dose from 10 pmol to 200 pmol, whereas tumor uptake remained unaffected. Notably, tumor values did not decline from 1 to 24 h pi; Conclusions: [67Ga]NeoBOMB1 can successfully target GRPR-positive breast cancer in animals with excellent prospects for clinical translation

68Ga/177Lu-NeoBOMB1, a novel radiolabeled GRPR antagonist for theranostic use in oncology

Because overexpression of the gastrin-releasing peptide receptor (GRPR) has been reported on various cancer types, for example, prostate cancer and breast cancer, targeting this receptor with radioligands might have a significant impact on staging and treatment of GRPR-expressing tumors. NeoBOMB1 is a novel DOTAcoupled GRPR antagonist with high affinity for GRPR and excellent in vivo stability. The purpose of this preclinical study was to further explore the use of NeoBOMB1 for theranostic application by determining the biodistribution of 68Ga-NeoBOMB1 and 177Lu- NeoBOMB1. Methods: PC-3 tumor–xenografted BALB/c nu/nu mice were injected with either approximately 13 MBq/250 pmol 68Ga- NeoBOMB1 or a low (;1MBq/200pmol) versus high (;1MBq/10 pmol) peptide amount of 177Lu-NeoBOMB1, after which biodistribution and imaging studies were performed. At 6 time points (15, 30, 60, 120, 240, and 360 min for 68Ga-NeoBOMB1 and 1, 4, 24, 48, 96, and 168 h for 177Lu-NeoBOMB1) postinjection tumor and organ uptake was determined. To assess receptor specificity, additional groups of animals were coinjected with an excess of unlabeled NeoBOMB1. Results of the biodistribution studies were used to determine pharmacokinetics and dosimetry. Furthermore, PET/CT and SPECT/MRI were performed. Results: Injection of approximately 250 pmol 68Ga-NeoBOMB1 resulted in a tumor and pancreas uptake of 12.4 6 2.3 and 22.7 6 3.3 percentage injected dose per gram (%ID/g) of tissue, respectively, at 120 min after injection. 177Lu-NeoBOMB1 biodistribution studies revealed a higher tumor uptake (17.9 6 3.3 vs. 11.6 6 1.3 %ID/g of tissue at 240 min after injection) and a lower pancreatic uptake (19.8 6 6.9 vs. 105 6 13 %ID/g of tissue at 240 min after injection) with the higher peptide amount injected, leading to a significant increase in the absorbed dose to the tumor versus the pancreas (200 pmol, 570 vs. 265 mGy/ MBq; 10 pmol, 435 vs. 1393 mGy/MBq). Using these data to predict patient dosimetry, we found a kidney, pancreas, and liver exposure of 0.10, 0.65, and 0.06mGy/MBq, respectively. Imaging studies resulted in good visualization of the tumor with both 68Ga-NeoBOMB1 and 177Lu-NeoBOMB1. Conclusion: Our findings indicate that 68Ga- or 177Lu-labeled NeoBOMB1 is a promising radiotracer with excellent tumor uptake and favorable pharmacokinetics for imaging and therapy of GRPR-expressing tumors

Understanding Interventional Bronchoscopy

Pediatric flexible bronchoscopy as a diagnostic modality has become a standard tool in the armamentarium of the modern pediatric pulmonologist. However the feasibility of interventions through flexible bronchoscopy is emerging slowly as it is limited not only by the size of the pediatric bronchoscope and its working channel but also by the demarcation lines between flexible and rigid bronchoscopy. We organize this chapter on interventional bronchoscopy into the following broad topics: Use of flexible bronchoscopy for acquisition of diagnostic material.Bronchoscopy for removal of obstructive, noxious, or damaging materials from the airway or the lung.Management of the narrowed or obstructed airway: debridement, dilation, and stenting.Use of bronchoscopy for other procedures including: sealing of fistulae and pneumothorax, control of diffuse alveolar hemorrhage, and segmental bronchography.New horizons: a discussion on recent reports on fetal bronchoscopy as a novel interventional approach

Randomized study of traditional versus aggressive systolic blood pressure control (Cardio-Sis): rationale, design and characteristics of the study population. Cardio-Sis Study Group

The hypothesis that a therapeutic strategy aimed at lowering systolic blood pressure (SBP) below 130 mm Hg is superior to a conventional strategy targeted at below 140 mm Hg in hypertensive subjects has never been tested in randomized intervention studies. The Studio Italiano Sugli Effetti Cardiovascolari del Controllo della Pressione Arteriosa Sistolica (Cardio-Sis) is a multi-centre study in non-diabetic, treated hypertensive subjects aged >55 years with uncontrolled SBP (>or=150 mm Hg) and at least one additional cardiovascular risk factor (ClinicalTrials.gov identifier: NCT00421863). Subjects are randomized to an SBP goal <140 mm Hg (conventional) or <130 mm Hg (aggressive), independently of baseline and achieved diastolic blood pressure (BP). Anti-hypertensive drugs dispensed for the study are restricted to a list of specific drugs. The primary outcome of the study is based on regression of left ventricular hypertrophy (LVH) using electrocardiography (ECG). The hypothesis is that subjects without LVH regression or with new development of LVH 2 years after randomization are 19% with conventional strategy and 12% with aggressive strategy. Secondary outcome is a composite pool of pre-specified fatal and non-fatal events. Randomization of 1111 subjects was completed by February 2007. Mean age of subjects (41% men) at entry was 67 years. BP was 158/87 mm Hg (systolic/diastolic) and prevalence of LVH by ECG was 21.0%. Cardio-Sis is the first randomized study specifically designed to compare two different SBP goals. Results will be broadly applicable to subjects with uncontrolled SBP under anti-hypertensive treatment

MEDICAL SCIENCE. GISSI-2: A factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12 490 patients with acute myocardial infarction

A multicentre, randomised, open trial with a 2 x 2 factorial design was conducted to compare the benefits and risks of two thrombolytic agents, streptokinase (SK, 1\ub75 MU infused intravenously over 30-60 min) and alteplase (tPA, 100 mg infused intravenously over 3 h) in patients with acute myocardial infarction admitted to coronary care units within 6 h from onset of symptoms. The patients were also randomised to receive heparin (12 500 U subcutaneously twice daily until discharge from hospital, starting 12 h after beginning the tPA or SK infusion) or usual therapy. All patients without specific contraindications were given atenolol (5-10 mg iv) and aspirin (300-325 mg a day). The end-point of the study was the combined estimate of death plus severe left ventricular damage. 12 490 patients were randomised to four treatment groups (SK alone, SK plus heparin, tPA alone, tPA plus heparin). No specific differences between the two thrombolytic agents were detected as regards the combined end-point (tPA 23\ub71%; SK 22\ub75%; relative risk 1\ub704, 95% Cl 0\ub795-1\ub713), nor after the addition of heparin to the aspirin treatment (hep 22\ub77%, no hep 22\ub79%; RR 0\ub799, 95% Cl 0\ub791-1\ub708). The outcome of patients allocated to the four treatment groups was similar with respect to baseline risk factors such as age, Killip class, hours from onset of symptoms, and site and type of infarct. The rates of major in-hospital cardiac complications (reinfarction, post-infarction angina) were also similar. The incidence of major bleeds was significantly higher in SK and heparin treated patients (respectively, tPA 0\ub75%, SK 1\ub70%, RR 0\ub757, 95% Cl 0\ub738-0\ub785; hep 1\ub70%, no hep 0\ub76%, RR 1\ub764, 95% Cl 1\ub709-2\ub745), whereas the overall incidence of stroke was similar in all groups. SK and tPA appear equally effective and safe for use in routine conditions of care, in all infarct patients who have no contraindications, with or without post-thrombolytic heparin treatment. The 8\ub78% hospital mortality of the study population (compared with approximately 13% in the control cohort of the GISSI-1 trial) indicates the beneficial impact of the proven acute treatments for AMI. \ua9 1990

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P &lt; 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)