CHARIOT: a phase I study of berzosertib with chemoradiotherapy in oesophageal and other solid cancers using time to event continual reassessment method.

BACKGROUND: Berzosertib (M6620) is a highly potent (IC50 = 19 nM) and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. This trial assessed the safety, preliminary efficacy, and tolerance of berzosertib in oesophageal cancer (A1 cohort) with RT and advanced solid tumours (A2 cohort) with cisplatin and capecitabine. METHODS: Single-arm, open-label dose-escalation (Time-to-Event Continual Reassessment Method) trial with 16 patients in A1 and 18 in A2. A1 tested six dose levels of berzosertib with RT (35 Gy over 15 fractions in 3 weeks). RESULTS: No dose-limiting toxicities (DLTs) in A1. Eight grade 3 treatment-related AEs occurred in five patients, with rash being the most common. The highest dose (240 mg/m2) was determined as the recommended phase II dose (RP2D) for A1. Seven DLTs in two patients in A2. The RP2D of berzosertib was 140 mg/m2 once weekly. The most common grade ≥3 treatment-related AEs were neutropenia and thrombocytopenia. No treatment-related deaths were reported. CONCLUSIONS: Berzosertib combined with RT is feasible and well tolerated in oesophageal cancer patients at high palliative doses. Berzosertib with cisplatin and capecitabine was well tolerated in advanced cancer. Further investigation is warranted in a phase 2 setting. CLINICAL TRIALS IDENTIFIER: EU Clinical Trials Register (EudraCT) - 2015-003965-27 ClinicalTrials.gov - NCT03641547.

Second-harmonic generation imaging of collagen in ancient bone.

Second-harmonic generation imaging (SHG) captures triple helical collagen molecules near tissue surfaces. Biomedical research routinely utilizes various imaging software packages to quantify SHG signals for collagen content and distribution estimates in modern tissue samples including bone. For the first time using SHG, samples of modern, medieval, and ice age bones were imaged to test the applicability of SHG to ancient bone from a variety of ages, settings, and taxa. Four independent techniques including Raman spectroscopy, FTIR spectroscopy, radiocarbon dating protocols, and mass spectrometry-based protein sequencing, confirm the presence of protein, consistent with the hypothesis that SHG imaging detects ancient bone collagen. These results suggest that future studies have the potential to use SHG imaging to provide new insights into the composition of ancient bone, to characterize ancient bone disorders, to investigate collagen preservation within and between various taxa, and to monitor collagen decay regimes in different depositional environments.

Management of native warm-season grasses for beef cattle and biomass production in the Mid-South USA.

Native grasses, such as switchgrass (SG; L.), big bluestem (BB; Vitman), indiangrass (IG; Nash), and eastern gamagrass (EG; [L.] L.) may be capable of providing desirable summer forage for cattle as well as a source of biomass for renewable energy. To evaluate that potential, experiments were conducted at 2 locations in Tennessee comparing weaned beef () steers (268 ± 25 kg initial BW) during early-season grazing (Early; 30 d, typically corresponding to May, followed by postdormancy biomass harvest) and full-season grazing (Full, mean duration = 98 d). For Exp. 1, which compared SG, a blend of BB and IG (BBIG), and EG, ADG was greater ( < 0.05) for BBIG (1.02 kg/d) than SG (0.85 kg/d), and both were greater ( < 0.05) than EG (0.66 kg/d). Grazing days for SG and EG were similar (389 and 423 animal unit days [AUD]/ha, respectively) and exceeded ( < 0.05) that of BBIG (233 AUD/ha) during Full. In Exp. 2 (SG and BBIG only), rates of gain were comparable to that of Exp. 1, but AUD were 425 (SG) and 299 (BBIG) AUD/ha. Such rates of gain and grazing days indicate that these grasses can provide desirable summer forage for growing cattle. Early produced 211 to 324 kg BW gain/ha, depending on experiment and forage, followed by dormant-season harvests of 7.5 to 10.5 Mg/ha of biomass, indicating a potential for beef cattle forage and biomass production on the same land resource. Native grasses provided productive summer pasture and good rates of gain on growing cattle and could contribute to forage programs, especially where cool-season grasses currently predominate.

Use of probiotics to reduce faecal shedding of Shiga toxin-producing Escherichia coli in sheep.

Shiga toxin-producing Escherichia coli (STEC) are zoonotic, foodborne pathogens of humans. Ruminants, including sheep, are the primary reservoirs of STEC and there is a need to develop intervention strategies to reduce the entry of STEC into the food chain. The initiation of the majority of bacterial, enteric infections involves colonisation of the gut mucosal surface by the pathogen. However, probiotic bacteria can serve to decrease the severity of infection via a number of mechanisms including competition for receptors and nutrients, and/or the synthesis of organic acids and bacteriocins that create an environment unfavourable for pathogen development. The aim of the current study was to determine whether the administration of a probiotic mixture to sheep experimentally infected with a non-O157 STEC strain, carrying stx1, stx2 and eae genes, was able to decrease faecal shedding of the pathogen. The probiotic mixture contained Lactobacillus acidophilus, Lactobacillus helveticus, Lactobacillus bulgaricus, Lactobacillus lactis, Streptococcus thermophilus and Enterococcus faecium. The numbers of non-O157 STEC in faecal samples collected from sheep receiving daily doses of the probiotic mixture were significantly lower at the 3rd, 5th and 6th week post-inoculation when compared to the levels recorded in untreated animals. It was concluded that administration of the probiotic mixture reduced faecal shedding of non-O157 STEC in sheep, and holds potential as a pre-harvest intervention method to reduce transmission to humans.

Treatment of diffuse systemic sclerosis with hyperimmune caprine serum (AIMSPRO): a phase II double-blind placebo-controlled trial.

OBJECTIVE: The primary objective of the study was to explore safety and tolerability of hyperimmune caprine serum (AIMSPRO) in established diffuse cutaneous systemic sclerosis (SSc). Secondary objectives included assessment of potential efficacy and biological activity and exploration of candidate biomarkers. METHODS: This was a double-blind parallel group randomised placebo-controlled clinical trial. After informed consent 20 patients with established diffuse cutaneous SSc of greater than 3 years duration not receiving immunosuppressive therapy were randomised to receive either active (n=10) or placebo formulation (n=10) by subcutaneous twice weekly injection over 26 weeks. Clinical assessments were evaluated over 26 weeks. RESULTS: There were no safety concerns during this study. Frequency of adverse events was not different between active and placebo groups. Mean modified Rodnan Skin Score (mRSS) fell by 1.4±4.7 units with active treatment but increased by 2.1±6.4 units on placebo when baseline values were compared with 26 weeks and responder analysis showed clinically meaningful improvement in mRSS at 26 weeks in 5 (50%) of actively treated patients compared with 1 (10%) in the control group (p=0.062). PIIINP (µg/L) showed a comparatively larger increase in the treatment group compared with the placebo group, (p=0.0118). CONCLUSIONS: These results confirm tolerability and safety of this novel biological agent in established diffuse SSc. The value of a placebo treated control group in small clinical trials evaluating skin disease in SSc is confirmed. Potential improvement in mRSS and changes in PIIINP in cases receiving active therapy suggest that this intervention may be of clinical benefit and warrants further evaluation.

Quantifying screening ion excesses in single-molecule force-extension experiments.

We derive a thermodynamic identity that allows one to infer the change in the number of screening ions that are associated with a charged macromolecule as the macromolecule is continuously stretched. Applying this identity to force-extension data on both single-stranded and double-stranded DNA, we find that the number of polymer-associated ions depends nontrivially on both the bulk salt concentration and the bare rigidity of the polymer, with single-stranded DNA exhibiting a relatively large decrease in ion excess upon stretching. We rationalize these observations using simple models for polyelectrolyte extension.

Attributes of response in depressed patients switched to treatment with duloxetine.

BACKGROUND: This study was designed to assess clinical and functional outcomes associated with switching to duloxetine treatment in patients with major depressive disorder (MDD) experiencing emotional and painful physical symptoms in their current episode. METHODS: In this 8-week, multinational, multicentre, single-arm, open-label clinical trial, 242 MDD patients were switched to duloxetine 60 mg/day after selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI) treatment. The primary analysis compared mean change from baseline in Brief Pain Inventory-Modified Short Form (BPI-SF) interference score between initial responders [≥ 50% reduction from baseline on the 17-item Hamilton Depression Rating Scale (HAMD(17)) Maier subscale] and initial non-responders after 4 weeks. Initial responders continued with duloxetine 60 mg/day. Initial non-responders received duloxetine 120 mg/day for the remaining 4 weeks. Depression, pain, anxiety and functional outcomes were also compared after 8 weeks. RESULTS: BPI-SF interference decreased from baseline in initial responders (n = 108) and initial non-responders (n = 85) after 4 weeks of duloxetine treatment, with greater reductions in initial responders [BPI-SF mean difference in reduction: 1.01 (95% CI 0.42-1.61); p < 0.001]. Reductions in pain interference favouring initial responders were also apparent after 8 weeks [0.68 (95% CI: 0.03-1.33); p = 0.042]. Depression, pain, anxiety and function improved over 8 weeks across patient groups. CONCLUSIONS: Elements of core mood and pain are important residual symptoms following poor treatment response in MDD. Early improvement in these symptoms after switching to duloxetine indicated an increased chance of functional recovery.

Detailed scaling analysis of low-force polyelectrolyte elasticity.

Single-molecule force-extension data are typically compared to ideal models of polymer behavior that ignore the effects of self-avoidance. Here, we demonstrate a link between single-molecule data and the scaling pictures of a real polymer. We measure a low-force elasticity regime where the extension L of chemically denatured single-stranded DNA grows as a power law with force f : L approximately f;{gamma} , with gamma approximately 0.60-0.69 . This compares favorably with the "tensile-blob" model of a self-avoiding polymer, which predicts gamma=2/3 . We show that the transition out of the low-force regime is highly salt dependent, and use the tensile-blob model to relate this effect to the salt dependence of the polymer's Kuhn length and excluded-volume parameter. We find that, contrary to the well-known Odijk-Skolnick-Fixman theory, the Kuhn length of single-stranded DNA is linearly proportional to the Debye length of the solution. Finally, we show that the low-force elasticity becomes linear (gamma=1) at approximately 3 M salt, and interpret this as a Theta point of the polymer. At this point, the force-extension data is best described by the wormlike chain model, from which we estimate the bare (nonelectrostatic) persistence length of the polymer to be approximately 0.6 nm .

Emergency abdominal aortic aneurysm presenting without haemodynamic shock is associated with misdiagnosis and delay in appropriate clinical management.

BACKGROUND: Emergency abdominal aortic aneurysm (EmAAA) represents a spectrum of disease from symptomatic non-ruptured aneurysms to free intraperitoneal rupture, with significantly worse outcomes for patients in a haemodynamically shocked state before surgery. A study was undertaken to see if the preoperative journey and outcome were different in patients who deviated from the classic acutely shocked presentation. METHODS: An observational database compiled from case notes of patients undergoing surgery for EmAAA at Sunderland Royal Hospital between April 2000 and October 2006 was interrogated to examine details of patient preoperative journey, physiological status and 30-day survival. Comparison between groups was performed using chi(2) analysis and the Mann-Whitney U test where appropriate. RESULTS: Records for 98 patients were available for review. Overall 30-day mortality was 49%, and was significantly higher for patients in shock at induction of anaesthesia than in those who were haemodynamically stable (59.6% vs 34.1%, p = 0.01). At presentation, 56 patients were stable and misdiagnosis was significantly more common in these patients than in those who were in shock (58.9% vs 26.2%, p = 0.002), with a significantly increased median time delay from presentation to diagnosis (144 min (IQR 24-366) vs 12 min (IQR 0-42), p<0.0001). Median time from diagnosis to arrival in theatre was significantly longer in patients who were haemodynamically stable at presentation (90 min (IQR 60-150) vs 48 min (IQR 36-90), p = 0.02). Of the 56 patients who were haemodynamically stable at presentation, 19 underwent haemodynamic decompensation before surgery with a significantly increased mortality compared with those who remained stable (73.7% vs 37.8%, p = 0.02). Of these 19 patients, only 5 were correctly diagnosed at presentation. CONCLUSIONS: Diagnosis and treatment of EmAAA in haemodynamically stable patients is often delayed, with the risk of significant rupture and haemodynamic decompensation which is associated with poor outcome. Correct diagnosis and treatment before development of shock has the potential to reduce mortality.

Nonlinear low-force elasticity of single-stranded DNA molecules.

We reconcile single-molecule force-extension data with scaling theories of polymer elasticity: measurements of denatured single-stranded DNA show a regime where the extension grows as a nonlinear power law with force, in accordance with "tensile blob" models. Analysis of the salt dependence of this regime indicates that the polymer's Kuhn length is proportional to the Debye length; this contradicts the Odijk-Skolnick-Fixman theory, but agrees with other predictions. Finally, we identify a Theta condition of the polymer, and find that the wormlike chain model best describes the polymer's elasticity at this point.

Epitaxially-grown Ge/Si avalanche photodiodes for 1.3 microm light detection.

We designed and fabricated Ge/Si avalanche photodiodes grown on silicon substrates. The mesa-type photodiodes exhibit a responsivity at 1310 nm of 0.54 A/W, a breakdown voltage thermal coefficient of 0.05%/ degrees C, a 3 dB-bandwidth of 10 GHz. The gain-bandwidth product was measured as 153 GHz. The effective k value extracted from the excess noise factor was 0.1.

Paediatric pre- and post-septal peri-orbital infections are different diseases. A retrospective review of 262 cases.

OBJECTIVE: Peri-orbital infections can be classified as pre-septal or post-septal depending upon the location of the focus of infection. The ability to differentiate between these two is frequently difficult at the initial presentation, with marked orbital edema and pain limiting the ophthalmic examination. Hence, it is important to identify all the features at presentation that will lead to an accurate and rapid diagnosis and treatment. Our retrospective review of peri-orbital infections identifies contrasting features between these two groups that will aid the clinician in the subsequent management of these infections. DESIGN AND SETTING: A retrospective review over an 11-year period of children admitted to a tertiary children's hospital for the treatment of peri-orbital cellulitis was undertaken. The two subgroups were identified, those suffering from a pre-septal infection and those with a post-septal infection. The groups were compared with respect to their presentation, clinical findings, findings on CT and surgical intervention. RESULTS: Two hundred and sixty-two children were identified with peri-orbital infections, 227 pre-septal, and 35 post-septal. There were statistically significant differences between the pre- and post-septal groups with regards to the following: age (3.9 vs. 7.5 years, p<0.001), medical co-morbidities (19% vs. 0%, p<0.01), a history of trauma (40% vs. 11% of cases, p<0.003), clinical diagnosis of acute sinusitis (9% vs. 91% of cases, p<0.001), and fever (47% vs. 94%, p<0.001). Ophthalmologic examination identified diplopia (p<0.001), opthalmoplegia (p<0.001) and proptosis (p<0.001) as significant features of a post-septal infection. Intravenous antibiotics were successful in treating the majority of cases, with 5% of pre-septal, and 25% of post-septal infections requiring surgery. CONCLUSION: When considering the management of a child with a peri-orbital infection, features from the history and examination such as trauma, medical co-morbidities and ophthalmic signs will guide management and delineate the indications for early CT imaging. In the absence of acute visual compromise or other signs of disease progression, initial management with intravenous antibiotics for 48 h to cover Staphylococcal aureus and Streptococcal pyogenes with nasal decongestant should be considered before surgical intervention is contemplated. A multi team approach is essential in obtaining the best outcome for the child.

Failure of contrast enhanced computed tomography scans to identify an orbital abscess. The benefit of magnetic resonance imaging.

INTRODUCTION: Acute sinusitis is a relatively common condition, which usually responds to medical therapy. In most cases, there are no sequelae or complications subsequent to this infection. However, like many acute illnesses, there are well documented complications of acute sinusitis, and in particular these include peri-orbital and intracranial spread. OBJECTIVE: The purpose of this paper is to highlight the importance of vigilance in peri-orbital involvement and the limitations of imaging techniques, such as computed tomography scanning. An illustrative case is presented to demonstrate this. CONCLUSION: Magnetic resonance imaging scanning is a valuable modality in assessing complex presentations of peri-orbital complications of acute sinusitis.

Acute orbital complications of sinusitis: the benefits of magnetic resonance imaging.

INTRODUCTION: Acute sinusitis is a relatively common condition, which usually responds to medical therapy. In most cases, there are no sequelae or complications subsequent to this infection. However, like many acute illnesses, there are well documented complications of acute sinusitis, and in particular these include peri-orbital and intracranial spread. OBJECTIVE: The purpose of this paper is to highlight the importance of vigilance regarding both peri-orbital involvement of sinusitis and the limitations of imaging techniques such as computed tomography. An illustrative case is presented to demonstrate this. CONCLUSION: Magnetic resonance imaging is a valuable modality in assessing complex presentations of peri-orbital complications of acute sinusitis.

External carotid artery blood supply to the orbit.

The utility of angiography and embolisation of selected branches of the external carotid artery is occasionally helpful in the management of recurrent epistaxis, pre-operative devascularisation of tumours such as angiofibromas, and other head and neck conditions. The use of embolisation for recalcitrant post-tonsillectomy bleeding due to the formation of an aneurysm or pseudoaneurysm of branches of the external carotid artery has been described [P. Simoni, J. Bello, B. Kent, Pseudoaneurysm of the lingual artery secondary to tonsillectomy treated with selective embolization, Int. J. Pediatr. Otorhinolaryngol. 59 (2) (2001) 125-128]. There are also reports of pseudoaneurysm formation on the internal carotid following tonsillectomy [F. Tovi, A. Leiberman, Y. Hertzanu, L. Golcman, Pseudoaneurysm of the internal carotid artery secondary to tonsillectomy, Int. J. Pediatr. Otolaryngol. 13 (1987) 69-75]. The repeated presentation of a 5-year-old girl with post-operative tonsillectomy bleeding on three separate occasions, each approximately 1 week apart, prompted the consideration of the diagnosis of aneurysm formation, and hence, angiography was performed. The anomalous finding from this study precluded embolisation due to the risk of blindness. This experience has prompted this review which highlights the important issues of angiographic assessment prior to embolisation. The relevance of this to external carotid artery ligation is also reflected upon.

Frontal sinus mini-trephination for acute sinusitis complicated by intracranial infection.

INTRODUCTION: Acute bacterial sinusitis is common in the pediatric population. Intracranial spread of infection is a rare but life-threatening complication of acute sinusitis. Due to the infrequent presentation of this complication, there are no well-defined management protocols for the acute sinusitis. CASE SERIES: We present three pediatric cases where children presented with intracranial sepsis, and the underlying source of infection was from the paranasal sinuses. In all cases, endoscopic sinus surgery was performed in the acute setting, with the use of frontal sinus mini-trephines playing a significant role. DISCUSSION: We describe our experience and review the available literature.