Metformin and the risk of head and neck cancer: a case-control analysis

AIMS Metformin use has been associated with a decreased risk of some cancers, although data on head and neck cancer (HNC) are scarce. We explored the relation between the use of antidiabetic drugs and the risk of HNC. METHODS We conducted a case-control analysis in the UK-based Clinical Practice Research Datalink (CPRD) of people with incident HNC between 1995 and 2013 below the age of 90 years. Six controls per case were matched on age, sex, calendar time, general practice and number of years of active history in the CPRD prior to the index date. Other potential confounders including body mass index (BMI), smoking, alcohol consumption and comorbidities were also evaluated. The final analyses were adjusted for BMI, smoking and diabetes mellitus (or diabetes duration in a sensitivity analysis). Results are presented as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS Use of metformin was neither associated with a statistically significant altered risk of HNC overall (1-29 prescriptions: adjusted OR 0.87, 95% CI 0.61-1.24 and ≥ 30 prescriptions adjusted OR 0.80, 95% CI 0.53-1.22), nor was long-term use of sulphonylureas (adjusted OR 0.87, 95% CI 0.59-1.30), or any insulin use (adjusted OR 0.92, 95% CI 0.63-1.35). However, we found a (statistically non-significant) decreased risk of laryngeal cancer associated with long-term metformin use (adjusted OR 0.41, 95% CI 0.17-1.03). CONCLUSIONS In this population-based study, the use of antidiabetic drugs was not associated with a materially altered risk of HNC. Our data suggest a protective effect of long-term metformin use for laryngeal cancer.

Horizontal head titubation in infants with Joubert syndrome: a new finding

AIM Head thrusts are well documented in Joubert syndrome and ocular motor apraxia. We provide a detailed clinical characterization of head titubation in 13 young children with Joubert syndrome. METHOD Detailed characterization of head titubation was assessed by targeted clinical evaluation and/or analysis of videos. RESULTS In 12 of 13 children (eight males, five females; median age 6y, range 2mo-15y) head titubation was first recognized in the first 2 months of age and decreased in severity until spontaneous resolution. In all children, the head titubation was horizontal, high frequency (~3Hz), had small amplitude (5-10°), was never present during sleep, and did not interfere with the neurodevelopment during infancy. In the majority of children, emotion, anxiety, and tiredness were worsening factors for head titubation. INTERPRETATION Head titubation is a benign, early presentation of Joubert syndrome. Head titubation in hypotonic infants should prompt a careful search for Joubert syndrome. Awareness of its occurrence in Joubert syndrome may avoid unnecessary investigations.

Radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: a randomised multicentre trial.

BACKGROUND It is unclear whether radial compared with femoral access improves outcomes in unselected patients with acute coronary syndromes undergoing invasive management. METHODS We did a randomised, multicentre, superiority trial comparing transradial against transfemoral access in patients with acute coronary syndrome with or without ST-segment elevation myocardial infarction who were about to undergo coronary angiography and percutaneous coronary intervention. Patients were randomly allocated (1:1) to radial or femoral access with a web-based system. The randomisation sequence was computer generated, blocked, and stratified by use of ticagrelor or prasugrel, type of acute coronary syndrome (ST-segment elevation myocardial infarction, troponin positive or negative, non-ST-segment elevation acute coronary syndrome), and anticipated use of immediate percutaneous coronary intervention. Outcome assessors were masked to treatment allocation. The 30-day coprimary outcomes were major adverse cardiovascular events, defined as death, myocardial infarction, or stroke, and net adverse clinical events, defined as major adverse cardiovascular events or Bleeding Academic Research Consortium (BARC) major bleeding unrelated to coronary artery bypass graft surgery. The analysis was by intention to treat. The two-sided α was prespecified at 0·025. The trial is registered at ClinicalTrials.gov, number NCT01433627. FINDINGS We randomly assigned 8404 patients with acute coronary syndrome, with or without ST-segment elevation, to radial (4197) or femoral (4207) access for coronary angiography and percutaneous coronary intervention. 369 (8·8%) patients with radial access had major adverse cardiovascular events, compared with 429 (10·3%) patients with femoral access (rate ratio [RR] 0·85, 95% CI 0·74-0·99; p=0·0307), non-significant at α of 0·025. 410 (9·8%) patients with radial access had net adverse clinical events compared with 486 (11·7%) patients with femoral access (0·83, 95% CI 0·73-0·96; p=0·0092). The difference was driven by BARC major bleeding unrelated to coronary artery bypass graft surgery (1·6% vs 2·3%, RR 0·67, 95% CI 0·49-0·92; p=0·013) and all-cause mortality (1·6% vs 2·2%, RR 0·72, 95% CI 0·53-0·99; p=0·045). INTERPRETATION In patients with acute coronary syndrome undergoing invasive management, radial as compared with femoral access reduces net adverse clinical events, through a reduction in major bleeding and all-cause mortality. FUNDING The Medicines Company and Terumo.

Fusion of fundus images and MRI data of the human eye

Purpose Ophthalmologists are confronted with a set of different image modalities to diagnose eye tumors e.g., fundus photography, CT and MRI. However, these images are often complementary and represent pathologies differently. Some aspects of tumors can only be seen in a particular modality. A fusion of modalities would improve the contextual information for diagnosis. The presented work attempts to register color fundus photography with MRI volumes. This would complement the low resolution 3D information in the MRI with high resolution 2D fundus images. Methods MRI volumes were acquired from 12 infants under the age of 5 with unilateral retinoblastoma. The contrast-enhanced T1-FLAIR sequence was performed with an isotropic resolution of less than 0.5mm. Fundus images were acquired with a RetCam camera. For healthy eyes, two landmarks were used: the optic disk and the fovea. The eyes were detected and extracted from the MRI volume using a 3D adaption of the Fast Radial Symmetry Transform (FRST). The cropped volume was automatically segmented using the Split Bregman algorithm. The optic nerve was enhanced by a Frangi vessel filter. By intersection the nerve with the retina the optic disk was found. The fovea position was estimated by constraining the position with the angle between the optic and the visual axis as well as the distance from the optic disk. The optical axis was detected automatically by fitting a parable on to the lens surface. On the fundus, the optic disk and the fovea were detected by using the method of Budai et al. Finally, the image was projected on to the segmented surface using the lens position as the camera center. In tumor affected eyes, the manually segmented tumors were used instead of the optic disk and macula for the registration. Results In all of the 12 MRI volumes that were tested the 24 eyes were found correctly, including healthy and pathological cases. In healthy eyes the optic nerve head was found in all of the tested eyes with an error of 1.08 +/- 0.37mm. A successful registration can be seen in figure 1. Conclusions The presented method is a step toward automatic fusion of modalities in ophthalmology. The combination enhances the MRI volume with higher resolution from the color fundus on the retina. Tumor treatment planning is improved by avoiding critical structures and disease progression monitoring is made easier.

Details of left ventricular radial wall motion supporting the ventricular theory of the third heart sound obtained by cardiac MR.

OBJECTIVE Obtaining new details of radial motion of left ventricular (LV) segments using velocity-encoding cardiac MRI. METHODS Cardiac MR examinations were performed on 14 healthy volunteers aged between 19 and 26 years. Cine images for navigator-gated phase contrast velocity mapping were acquired using a black blood segmented κ-space spoiled gradient echo sequence with a temporal resolution of 13.8 ms. Peak systolic and diastolic radial velocities as well as radial velocity curves were obtained for 16 ventricular segments. RESULTS Significant differences among peak radial velocities of basal and mid-ventricular segments have been recorded. Particular patterns of segmental radial velocity curves were also noted. An additional wave of outward radial movement during the phase of rapid ventricular filling, corresponding to the expected timing of the third heart sound, appeared of particular interest. CONCLUSION The technique has allowed visualization of new details of LV radial wall motion. In particular, higher peak systolic radial velocities of anterior and inferior segments are suggestive of a relatively higher dynamics of anteroposterior vs lateral radial motion in systole. Specific patterns of radial motion of other LV segments may provide additional insights into LV mechanics. ADVANCES IN KNOWLEDGE The outward radial movement of LV segments impacted by the blood flow during rapid ventricular filling provides a potential substrate for the third heart sound. A biphasic radial expansion of the basal anteroseptal segment in early diastole is likely to be related to the simultaneous longitudinal LV displacement by the stretched great vessels following repolarization and their close apposition to this segment.

Virtopsy--fatal motor vehicle accident with head injury.

A man wearing no protective helmet was struck by a motor vehicle while riding a bicycle. He was loaded on his left side, and the impact point of his head was his occiput on the car roof girder. He was immediately transported to the general hospital, where he passed away. Postmortem examination using multi-slice computed tomography (MSCT) revealed an extensively comminuted fracture of the posterior part and the base of the skull. Observed were deep direct and contrecoup brain bruises, with the independent fractures of the roof of the both orbits. Massive subdural and subarachnoidal hemorrhage with cerebral edema and shifting of the mid-line towards left side were also detected. MSCT and autopsy results were compared and the body injuries were correlated to vehicle damages. In conclusion, postmortem imaging is a good forensic visualization tool with great potential for documentation and examination of body injuries and pathology.

Lateral impact in closed head injury: A substantially increased risk for diffuse axonal injury—A preliminary study

OBJECTIVE: Assessment, whether location of impact causing different facial fracture patterns was associated with diffuse axonal injury in patients with severe closed head injury. METHODS: Retrospectively all patients referred to the Trauma Unit of the University Hospital of Zurich, Switzerland between 1996 and 2002 presenting with severe closed head injuries (Abbreviated Injury Scale (AIS) (face) of 2-4 and an AIS (head and neck) of 3-5) were assessed according to the Glasgow Coma Scale (GCS) and the Injury Severity Score (ISS). Facial fracture patterns were classified as resulting from frontal, oblique or lateral impact. All patients had undergone computed tomography. The association between impact location and diffuse axonal injury when correcting for the level of consciousness (using the Glasgow scale) and severity of injury (using the ISS) was calculated with a multivariate regression analysis. RESULTS: Of 200 screened patients, 61 fulfilled the inclusion criteria for severe closed head injury. The medians (interquartile ranges 25;75) for GCS, AIS(face) AIS(head and neck) and ISS were 3 (3;13), 2 (2;4), 4 (4;5) and 30 (24;41), respectively. A total of 51% patients had frontal, 26% had an oblique and 23% had lateral trauma. A total of 21% patients developed diffuse axonal injury (DAI) when compared with frontal impact, the likelihood of diffuse axonal injury increased 11.0 fold (1.7-73.0) in patients with a lateral impact. CONCLUSIONS: Clinicians should be aware of the substantial increase of diffuse axonal injury related to lateral impact in patients with severe closed head injuries.

Street crossing behavior in younger and older pedestrians: an eye- and head-tracking study

BACKGROUND: Crossing a street can be a very difficult task for older pedestrians. With increased age and potential cognitive decline, older people take the decision to cross a street primarily based on vehicles' distance, and not on their speed. Furthermore, older pedestrians tend to overestimate their own walking speed, and could not adapt it according to the traffic conditions. Pedestrians' behavior is often tested using virtual reality. Virtual reality presents the advantage of being safe, cost-effective, and allows using standardized test conditions. METHODS: This paper describes an observational study with older and younger adults. Street crossing behavior was investigated in 18 healthy, younger and 18 older subjects by using a virtual reality setting. The aim of the study was to measure behavioral data (such as eye and head movements) and to assess how the two age groups differ in terms of number of safe street crossings, virtual crashes, and missed street crossing opportunities. Street crossing behavior, eye and head movements, in older and younger subjects, were compared with non-parametric tests. RESULTS: The results showed that younger pedestrians behaved in a more secure manner while crossing a street, as compared to older people. The eye and head movements analysis revealed that older people looked more at the ground and less at the other side of the street to cross. CONCLUSIONS: The less secure behavior in street crossing found in older pedestrians could be explained by their reduced cognitive and visual abilities, which, in turn, resulted in difficulties in the decision-making process, especially under time pressure. Decisions to cross a street are based on the distance of the oncoming cars, rather than their speed, for both groups. Older pedestrians look more at their feet, probably because of their need of more time to plan precise stepping movement and, in turn, pay less attention to the traffic. This might help to set up guidelines for improving senior pedestrians' safety, in terms of speed limits, road design, and mixed physical-cognitive trainings.

Probing the Structure, Pseudorotation, and Radial Vibrations of Cyclopentane by Femtosecond Rotational Raman Coherence Spectroscopy

Femtosecond time-resolved Raman rotational coherence spectroscopy (RCS) is employed to determine accurate rotational, vibration–rotation coupling constants, and centrifugal distortion constants of cyclopentane (C⁵H¹⁰). Its lowest-frequency vibration is a pseudorotating ring deformation that interconverts 10 permutationally distinct but energetically degenerate “twist” minima interspersed by 10 “bent” conformers. While the individual twist and bent structures are polar asymmetric tops, the pseudorotation is fast on the time scale of external rotation, rendering cyclopentane a fluxionally nonpolar symmetric top molecule. The pseudorotational level pattern corresponds to a one-dimensional internal rotor with a pseudorotation constant Bps ≈ 2.8 cm⁻¹. The pseudorotational levels are significantly populated up to l = ± 13 at 298 K; <10% of the molecules are in the l = 0 level. The next-higher vibration is the “radial” ν²³ ring deformation mode at 273 cm⁻¹, which is far above the pseudorotational fundamental. Femtosecond Raman RCS measurements were performed in a gas cell at T = 293 K and in a pulsed supersonic jet at T ≈ 90 K. The jet cooling reduces the pseudorotational distribution to l < ±8 and eliminates the population of ν²³, allowing one to determine the rotational constant as A0 = B0 = 6484.930(11) MHz. This value is ∼300 times more precise than the previous value. The fit of the RCS transients reveals that the rotation–pseudorotation coupling constant αe,psB = −0.00070(1) MHz is diminutive, implying that excitation of the pseudorotation has virtually no effect on the B0 rotational constant of cyclopentane. The smallness of αe,psB can be realized when comparing to the vibration–rotation coupling constant of the ν²³ vibration, αe,23B = −9.547(1) MHz, which is about 10⁴ times larger.

Treatment of posttraumatic cubitus varus in children and adolescents. Supracondylar humeral osteotomy using radial external fixation

OBJECTIVE Precise adaptable fixation of a supracondylar humerus osteotomy with a radial/lateral external fixator to correct posttraumatic cubitus varus. INDICATIONS Acquired, posttraumatic cubitus varus as a result of a malhealed and unsatisfactorily treated supracondylar humerus fracture. Idiopathic, congenital cubitus varus (very seldom) if the child (independent of age and after complete healing) is cosmetically impaired; stability of the elbow is reduced due to malalignment (hyperextension); secondary problems and pain (e. g., irritation of the ulnar nerve) are expected or already exist; or there is an explicit wish of the child/parents (relative indication). CONTRAINDICATIONS In principle there are no contraindications provided that the indication criteria are filled. The common argument of age does not represent a contraindication in our opinion, since angular remodeling at the distal end of the humerus is practically nonexistent. SURGICAL TECHNIQUE Basically, the surgical technique of the radial external fixator is used as previously described for stabilization of complex supracondylar humeral fractures. With the patient in supine position, the arm is placed freely on an arm table. Using a 4-5 cm long skin incision along the radial, supracondylar, the extracapsular part of the distal humerus is prepared, whereby great caution regarding the radial nerve is advised. In contrast to the procedure used in radial external fixation for supracondylar humeral fracture treatment, two Schanz screws are always fixed in each fragment at a distance of 1.5-2 cm. The osteotomy must allow the fragment to freely move in all directions. The proximal and distal two Schanz screws are then connected with short 4 mm carbon or stainless steel rods. These two rods are connected with each other over another rod using the tub-to-tub technique. Now the preliminary correction according the clinical situation can be performed and the clamps are tightened. Anatomical axis and function are checked. If these are radiologically and clinically perfect, all clamps are definitively tightened; if the alignment or the function is not perfect, then further adjustments can be made. POSTOPERATIVE MANAGEMENT Due to the excellent stability, further immobilization not necessary. Immediate functional follow-up treatment performed according to pain. RESULTS Adequate healing is usually expected within 6 weeks. At this time the external fixator can be removed in the fracture clinic. Because the whole operation is performed in an extraarticular manner and the mobility of the elbow is not affected, deterioration of function has never been observed. Also regarding the cosmetic/anatomical situation, good results are expected because they were already achieved intraoperatively.

Impact of weight loss on survival after chemoradiation for locally advanced head and neck cancer: secondary results of a randomized phase III trial (SAKK 10/94).

BACKGROUND To analyze the impact of weight loss before and during chemoradiation on survival outcomes in patients with locally advanced head and neck cancer. METHODS From 07/1994-07/2000 a total of 224 patients with squamous cell carcinoma of the head and neck were randomized to either hyperfractionated radiation therapy alone or the same radiation therapy combined with two cycles of concomitant cisplatin. The primary endpoint was time to any treatment failure (TTF); secondary endpoints were locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS). Patient weight was measured 6 months before treatment, at treatment start and treatment end. RESULTS The proportion of patients with >5% weight loss was 32% before, and 51% during treatment, and the proportion of patients with >10% weight loss was 12% before, and 17% during treatment. After a median follow-up of 9.5 years (range, 0.1 - 15.4 years) weight loss before treatment was associated with decreased TTF, LRRFS, DMFS, cancer specific survival and OS in a multivariable analysis. However, weight loss during treatment was not associated with survival outcomes. CONCLUSIONS Weight loss before and during chemoradiation was commonly observed. Weight loss before but not during treatment was associated with worse survival.

Profiling invasiveness in head and neck cancer: recent contributions of genomic and transcriptomic approaches.

High-throughput molecular profiling approaches have emerged as precious research tools in the field of head and neck translational oncology. Such approaches have identified and/or confirmed the role of several genes or pathways in the acquisition/maintenance of an invasive phenotype and the execution of cellular programs related to cell invasion. Recently published new-generation sequencing studies in head and neck squamous cell carcinoma (HNSCC) have unveiled prominent roles in carcinogenesis and cell invasion of mutations involving NOTCH1 and PI3K-patwhay components. Gene-expression profiling studies combined with systems biology approaches have allowed identifying and gaining further mechanistic understanding into pathways commonly enriched in invasive HNSCC. These pathways include antigen-presenting and leucocyte adhesion molecules, as well as genes involved in cell-extracellular matrix interactions. Here we review the major insights into invasiveness in head and neck cancer provided by high-throughput molecular profiling approaches.