Adenomas from individuals with pathogenic biallelic variants in the MUTYH and NTHL1 genes demonstrate base excision repair tumour mutational signature profiles similar to colorectal cancers, expanding potential diagnostic and variant classification applications.

Background: Colorectal cancers (CRCs) from people with biallelic germline likely pathogenic/pathogenic variants in MUTYH or NTHL1 exhibit specific single base substitution (SBS) mutational signatures, namely combined SBS18 and SBS36 (SBS18+SBS36), and SBS30, respectively. The aim was to determine if adenomas from biallelic cases demonstrated these mutational signatures at diagnostic levels.

Methods: Whole-exome sequencing of FFPE tissue and matched blood-derived DNA was performed on 9 adenomas and 15 CRCs from 13 biallelic MUTYH cases, on 7 adenomas and 2 CRCs from 5 biallelic NTHL1 cases and on 27 adenomas and 26 CRCs from 46 non-hereditary (sporadic) participants.

Electrophysiological Activity from the Eye Muscles, Cerebellum and Cerebrum During Reflexive (Classical Pavlovian) Versus Voluntary (Ivanov-Smolensky) Eye-Blink Conditioning.

We report an experiment to investigate the role of the cerebellum and cerebrum in motor learning of timed movements. Eleven healthy human subjects were recruited to perform two experiments, the first was a classical eye-blink conditioning procedure with an auditory tone as conditional stimulus (CS) and vestibular unconditional stimulus (US) in the form of a double head-tap. In the second experiment, subjects were asked to blink voluntarily in synchrony with the double head-tap US preceded by a CS, a form of Ivanov-Smolensky conditioning in which a command or instruction is associated with the US.

Extended source analysis of movement related potentials (MRPs) for self-paced hand and foot movements demonstrates opposing cerebral and cerebellar laterality: a preliminary study.

The cerebellum is known to have extensive reciprocal connectivity with the cerebral cortex, including with prefrontal and posterior parietal cortex, which play an important role on the planning and execution of voluntary movement. In the present article we report an exploratory non-invasive electrophysiological study of the activity of the cerebellum and cerebrum during voluntary finger and foot movements. In a sample of five healthy adult subjects, we recorded EEG and the electro-cerebellogram (ECeG) with a 10% cerebellar extension montage during voluntary left and right index finger and foot movements.

Molecular typing of enteroviruses: comparing 5'UTR, VP1 and whole genome sequencing methods.

Enteroviruses (EV) commonly cause hand, foot and mouth disease (HFMD), and can also cause potentially fatal neurological and systemic complications. In our laboratory, sequencing 5' untranslated region (UTR) of the viral genome has been the routine method of genotyping EVs. During a recent localised outbreak of aseptic meningitis, sequencing the 5'UTR identified the causative virus as EV-A71, which did not fit with the clinical syndrome or illness severity.

How aging of the global population is changing oncology.

Population aging is causing a demographic redistribution with implications for the future of healthcare. How will this affect oncology? First, there will be an overall rise in cancer affecting older adults, even though age-specific cancer incidences continue to fall due to better prevention. Second, there will be a wider spectrum of health functionality in this expanding cohort of older adults, with differences between "physiologically older" and "physiologically younger" patients becoming more important for optimal treatment selection.

2b or Not 2b: How Opposing FGF Receptor Splice Variants Are Blocking Progress in Precision Oncology.

More than ten thousand peer-reviewed studies have assessed the role of fibroblast growth factors (FGFs) and their receptors (FGFRs) in cancer, but few patients have yet benefited from drugs targeting this molecular family. Strategizing how best to use FGFR-targeted drugs is complicated by multiple variables, including RNA splicing events that alter the affinity of ligands for FGFRs and hence change the outcomes of stromal-epithelial interactions. The effects of splicing are most relevant to FGFR2; expression of the FGFR2b splice isoform can restore apoptotic sensitivity to cancer cells, whereas switching to FGFR2c may drive tumor progression by triggering epithelial-mesenchymal transition.

Correction to: 3D-printed spine surgery implants: a systematic review of the efficacy and clinical safety profile of patient-specific and off-the-shelf devices.

Unfortunately, 3rd author's first name was incorrectly published in the original publication. The complete correct name is given below.

3D-printed spine surgery implants: a systematic review of the efficacy and clinical safety profile of patient-specific and off-the-shelf devices.

Purpose: Three-dimensional printing (3DP), or additive manufacturing, is an emergent fabrication technology for surgical devices. As a production method, 3DP enables physical realisation of surgical implants from geometrically complex digital-models in computer-aided design. Spine surgery has been an innovative adopter of 3DP technology for both patient-specific (PS) and market-available 'Off-The-Shelf' (OTS) implants.

Beyond competency-based continuing professional development.

Competency based medical education (CBME) has become the default for undergraduate and post-graduate medical education (PGME) but its role in continuing professional development (CPD) is under discussion. Some critical differences between CPD and PGME are identified and these differences applied to: the relative roles of competence and performance; existing criticisms of CBME; heutagogy as a learning theory; and post-modernism as an underlying philosophical perspective. The argument is made that the characteristics of CPD fit with performance based medical education, a heutagogical learning theory, a focus on capabilities, rather than competencies; and a post-modern perspective.

Quality of life during olaparib maintenance therapy in platinum-sensitive relapsed serous ovarian cancer.

Background: Maintenance monotherapy with the poly(ADP-ribose) polymerase inhibitor olaparib significantly prolongs progression-free survival over placebo in patients with platinum-sensitive relapsed serous ovarian cancer, with greatest benefit seen in patients with a BRCA1/2 mutation (BRCAm). Preservation of health-related quality of life (HRQoL) is important during maintenance therapy; we evaluated the effect of olaparib on HRQoL in this Phase II trial (NCT00753545, Study 19).

Methods: Patients received olaparib 400 mg b.

Anticancer activity of combination targeted therapy using cetuximab plus vemurafenib for refractory BRAF (V600E)-mutant metastatic colorectal carcinoma.

Mismatch-repair-deficient colorectal cancers often contain kinase-activating V600E BRAF mutations, but no clinical utility has yet been demonstrated in this setting for monotherapy using oral braf kinase inhibitors such as vemurafenib or dabrafenib. Recent studies have indicated that tumour resistance to braf inhibition is mediated by upregulated epidermal growth factor receptor (egfr) signalling, disruption of which is a routine treatment strategy in KRAS wild-type colorectal cancer. In this report, we describe the clinical course of a heavily pretreated patient who elected to receive off-label dual-targeted braf- and egfr-inhibitory therapy with good tolerance and apparent clinical benefit.

The unpluggable in pursuit of the undruggable: tackling the dark matter of the cancer therapeutics universe.

The notion that targeted drugs can unplug gain-of-function tumor pathways has revitalized pharmaceutical research, but the survival benefits of this strategy have so far proven modest. A weakness of oncogene-blocking approaches is that they do not address the problem of cancer progression as selected by the recessive phenotypes of genetic instability and apoptotic resistance which in turn arise from loss-of-function - i.e.

IAP/APA evidence-based guidelines for the management of acute pancreatitis.

Background: There have been substantial improvements in the management of acute pancreatitis since the publication of the International Association of Pancreatology (IAP) treatment guidelines in 2002. A collaboration of the IAP and the American Pancreatic Association (APA) was undertaken to revise these guidelines using an evidence-based approach.

Methods: Twelve multidisciplinary review groups performed systematic literature reviews to answer 38 predefined clinical questions.

Papillomavirus-associated squamous skin cancers following transplant immunosuppression: one Notch closer to control.

The frequent occurrence of cutaneous squamous cell carcinomas (SCCs) containing weakly tumorigenic human papillomaviruses (HPVs) following iatrogenic immunosuppression for organ transplantation remains incompletely understood. Here we address this problem in the light of recent insights into (1) the association of low-risk β-HPVs with skin SCCs in the rare genetic syndromes of epidermodysplasia verruciformis and xeroderma pigmentosum, (2) the frequent recovery of post-transplant tumor control on substituting calcineurin-inhibitory with mTOR-inhibitory immunosuppression, (3) the unexpectedly favorable prognosis of node-positive SCCs containing high-risk α-HPVs originating in the activated immune niche of the oropharynx, (4) the rapid occurrence of HPV-negative SCCs in ultraviolet (UV)-damaged skin of melanoma patients receiving Raf-inhibitory drugs, and (5) the selective ability of β-HPV E6 oncoproteins to inhibit Notch tumor-suppressive signaling in cutaneous and mesenchymal tissues. The crosstalk so implied between oncogenic UV-induced mutations, defective host immunity, and β-HPV-dependent stromal-epithelial signaling suggests that immunosuppressants such as calcineurin inhibitors intensify mitogenic signalling in TP53-mutant keratinocytes while also abrogating immune-dependent Notch-mediated tumor repression.

Vestibular hypersensitivity to sound in superior canal dehiscence: large evoked responses in the legs produce little postural sway.

Objective: Patients with superior canal dehiscence (SCD) typically have enhanced sound-evoked vestibular reflexes, such as vestibulo-collic and vestibulo-ocular reflexes. We wished to investigate whether sound-evoked lower limb EMG responses and postural sway are also enhanced in this condition.

Methods: Eight patients with CT confirmed SCD (11 affected ears) and 8 age-matched normal controls participated.

A source analysis of short-latency vestibular evoked potentials produced by air- and bone-conducted sound.

Objective: To map short-latency vestibular evoked potentials (VsEPs) using air- (AC) and bone-conducted (BC) sound and to perform source analysis to determine their origin.

Methods: Ten normal volunteers, chosen to have low-normal thresholds for acoustic vestibular activation, participated. In the first part, the subjects' individual thresholds for vestibular activation (V(T)) were established using vestibular evoked myogenic potentials (VEMPs) recorded from the sternocleidomastoid muscles.

Ocular vestibular evoked myogenic potentials in superior canal dehiscence.

Objective: Patients with superior canal dehiscence (SCD) have large sound-evoked vestibular reflexes with pathologically low threshold. We wished to determine whether a recently discovered measure of the vestibulo-ocular reflex-the ocular vestibular evoked myogenic potential (OVEMP)-produced similar high-amplitude, low-threshold responses in SCD, and could differentiate patients with SCD from normal control patients.

Methods: Nine patients with CT-confirmed SCD and 10 normal controls were stimulated with 500 Hz, 2 ms tone bursts and 0.

Delayed vestibular evoked responses to the eyes and neck in a patient with an isolated brainstem lesion.

Objective: Two recently described tests of the vestibular system, vestibular evoked myogenic potentials (VEMPs) and ocular vestibular evoked myogenic potentials (OVEMPs), test the descending and ascending vestibular brainstem pathways, respectively. We describe a case of a patient in whom these investigations localised the lesion and suggested its nature.

Methods: VEMPs (to clicks and short duration galvanic stimulation) and OVEMPs (to clicks) were recorded.

Cervical dystonia responsive to acoustic and galvanic vestibular stimulation.

We examined the effects of acoustic and galvanic vestibular stimulation in a patient with cervical dystonia. Acoustic stimulation consisted of three conditions: "baseline" (no stimulation), "vestibular" (500 Hz bone-conducted tone bursts), and "control" (5,000 Hz tone bursts). Rectified electromyographic activity in the sternocleidomastoid was measured.

Vestibular evoked potentials (VsEPs) in patients with severe to profound bilateral hearing loss.

Objective: To confirm the exclusive vestibular dependence of the evoked potentials (P10 and N15) recorded in normal subjects, by recording the potentials evoked in response to bone-conducted sound stimulation in patients with bilateral hearing loss.

Methods: Fourteen patients with severe to profound bilateral hearing loss were stimulated via a B71 bone-vibrator above the mastoid with bone-conducted tone bursts (500 Hz, 6 ms) at fixed levels above their individual vestibular evoked myogenic potential (VEMP) thresholds. Surface potentials were recorded from scalp electrodes at F7, F3, Fpz, F4, F8, T3, Cz, and T4 and referred to linked earlobes.

Vestibular-evoked extraocular potentials produced by stimulation with bone-conducted sound.

Objective: To investigate the origin, whether ocular or extraocular, of the short latency frontal potential (N15) reported by following vestibular stimulation.

Methods: Fourteen subjects with low VEMP thresholds (V(T)) and 9 patients with vestibular or ocular disorders were stimulated at the mastoid with bone-conducted tone bursts (500 Hz, 8 ms) above vestibular threshold, using a B71 bone vibrator. Surface potentials were recorded from Fpz and around the eyes and referred to linked earlobes.