A germline mutation in the 3′-untranslated region of KRAS (rs61764370, KRAS-variant: TG/GG) has previously been associated with altered patient outcome and drug resistance/sensitivity in various ...cancers. We examined the prognostic and predictive significance of this variant in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
We conducted a retrospective study of 103 HNSCCs collected from three completed clinical trials. KRAS-variant genotyping was conducted for these samples and 8 HNSCC cell lines. p16 expression was determined in a subset of 26 oropharynx tumors by immunohistochemistry. Microarray analysis was also utilized to elucidate differentially expressed genes between KRAS-variant and non-variant tumors. Drug sensitivity in cell lines was evaluated to confirm clinical findings.
KRAS-variant status was determined in 95/103 (92%) of the HNSCC tumor samples and the allelic frequency of TG/GG was 32% (30/95). Three of the HNSCC cell lines (3/8) studied had the KRAS-variant. No association between KRAS-variant status and p16 expression was observed in the oropharynx subset (Fisher's exact test, P = 1.0). With respect to patient outcome, patients with the KRAS-variant had poor progression-free survival when treated with cisplatin (log-rank P = 0.002). Conversely, KRAS-variant patients appeared to experience some improvement in disease control when cetuximab was added to their platinum-based regimen (log-rank P = 0.04).
The TG/GG rs61764370 KRAS-variant is a potential predictive biomarker for poor platinum response in R/M HNSCC patients.
NCT00503997, NCT00425750, NCT00003809.
ABSTRACT
The Vera C. Rubin Observatory Legacy Survey of Space and Time (LSST) will observe several Deep Drilling Fields (DDFs) to a greater depth and with a more rapid cadence than the main survey. ...In this paper, we describe the ‘DeepDrill’ survey, which used the Spitzer Space Telescope Infrared Array Camera (IRAC) to observe three of the four currently defined DDFs in two bands, centred on 3.6 and 4.5 μm. These observations expand the area that was covered by an earlier set of observations in these three fields by the Spitzer Extragalactic Representative Volume Survey (SERVS). The combined DeepDrill and SERVS data cover the footprints of the LSST DDFs in the Extended Chandra Deep Field–South (ECDFS) field, the ELAIS-S1 field (ES1), and the XMM-Large-Scale Structure Survey field (XMM-LSS). The observations reach an approximate 5σ point-source depth of 2 μJy (corresponding to an AB magnitude of 23.1; sufficient to detect a 10$^{11} \, \mathrm{M}_{\odot}$ galaxy out to z ≈ 5) in each of the two bands over a total area of $\approx 29\,$ deg2. The dual-band catalogues contain a total of 2.35 million sources. In this paper, we describe the observations and data products from the survey, and an overview of the properties of galaxies in the survey. We compare the source counts to predictions from the Shark semi-analytic model of galaxy formation. We also identify a population of sources with extremely red (3.6−4.5 >1.2) colours which we show mostly consists of highly obscured active galactic nuclei.
This study was designed to evaluate whether subjects with amyloid beta (Aβ) pathology, detected using florbetapir positron emission tomorgraphy (PET), demonstrated greater cognitive decline than ...subjects without Aβ pathology. Sixty-nine cognitively normal (CN) controls, 52 with recently diagnosed mild cognitive impairment (MCI) and 31 with probable Alzheimer's disease (AD) dementia were included in the study. PET images obtained in these subjects were visually rated as positive (Aβ+) or negative (Aβ-), blind to diagnosis. Fourteen percent (10/69) of CN, 37% (19/52) of MCI and 68% (21/31) of AD were Aβ+. The primary outcome was change in ADAS-Cog score in MCI subjects after 36 months; however, additional outcomes included change on measures of cognition, function and diagnostic status. Aβ+ MCI subjects demonstrated greater worsening compared with Aβ- subjects on the ADAS-Cog over 36 months (5.66 ± 1.47 vs -0.71 ± 1.09, P = 0.0014) as well as on the mini-mental state exam (MMSE), digit symbol substitution (DSS) test, and a verbal fluency test (P < 0.05). Similar to MCI subjects, Aβ+ CN subjects showed greater decline on the ADAS-Cog, digit-symbol-substitution test and verbal fluency (P<0.05), whereas Aβ+ AD patients showed greater declines in verbal fluency and the MMSE (P < 0.05). Aβ+ subjects in all diagnostic groups also showed greater decline on the CDR-SB (P<0.04), a global clinical assessment. Aβ+ subjects did not show significantly greater declines on the ADCS-ADL or Wechsler Memory Scale. Overall, these findings suggest that in CN, MCI and AD subjects, florbetapir PET Aβ+ subjects show greater cognitive and global deterioration over a 3-year follow-up than Aβ- subjects do.
Peripheral nerve injury (PNI) is a significant health problem that confers lifelong impact on those injured. Current interventions are purely surgical; however, outcomes remain poor. There is a lack ...of high-quality epidemiological data that is needed to identify populations involved, current healthcare demands, and ensure resources are distributed to the greatest effect, to reduce the injury burden.
Anonymized hospital episode statistical (HES) data on admitted patient care was obtained from NHS Digital for all National Health Service (NHS) patients sustaining PNI of all body regions between 2005 and 2020. Total numbers of finished consultant episodes (FCEs) or FCEs/100,000 population were used to demonstrate changes in demographic variables, anatomical locations of injury, mechanisms of injury, speciality, and main operation.
There was a mean national incidence of 11.2 (95% CI 10.9, 11.6) events per 100,000 population per year. Males were at least twice as likely (p < 0.0001) to sustain a PNI. Upper limb nerves at or distal to the wrist were most commonly injured. Knife injuries increased (p < 0.0001), whereas glass injuries decreased (p < 0.0001). Plastic surgeons increasingly managed PNI (p = 0.002) as opposed to orthopaedic surgeons (p = 0.006) or neurosurgeons (p = 0.001). There was an increase in neurosynthesis (p = 0.022) and graft procedures (p < 0.0001) during the study period.
PNI is a significant national healthcare problem predominantly affecting distal, upper limb nerves of men of working age. Injury prevention strategies, improved targeted funding and rehabilitation pathways are needed to reduce the injury burden and improve patient care.
Aims
To investigate the anorectic effect of L‐arginine (L‐Arg) in rodents.
Methods
We investigated the effects of L‐Arg on food intake, and the role of the anorectic gut hormones glucagon‐like ...peptide‐1 (GLP‐1) and peptide YY (PYY), the G‐protein‐coupled receptor family C group 6 member A (GPRC6A) and the vagus nerve in mediating these effects in rodents.
Results
Oral gavage of L‐Arg reduced food intake in rodents, and chronically reduced cumulative food intake in diet‐induced obese mice. Lack of the GPRC6A in mice and subdiaphragmatic vagal deafferentation in rats did not influence these anorectic effects. L‐Arg stimulated GLP‐1 and PYY release in vitro and in vivo. Pharmacological blockade of GLP‐1 and PYY receptors did not influence the anorectic effect of L‐Arg. L‐Arg‐mediated PYY release modulated net ion transport across the gut mucosa. Intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration of L‐Arg suppressed food intake in rats.
Conclusions
L‐Arg reduced food intake and stimulated gut hormone release in rodents. The anorectic effect of L‐Arg is unlikely to be mediated by GLP‐1 and PYY, does not require GPRC6A signalling and is not mediated via the vagus. I.c.v. and i.p. administration of L‐Arg suppressed food intake in rats, suggesting that L‐Arg may act on the brain to influence food intake. Further work is required to determine the mechanisms by which L‐Arg suppresses food intake and its utility in the treatment of obesity.
Population ageing is a global phenomenon. It is regarded as a major cause of upward pressure on healthcare costs. One of the greatest threats to healthy, independent ageing is sarcopenia, the ...progressive loss of skeletal muscle mass and function with age. Physical inactivity and poor nutrition represent crucial and imminently modifiable risk factors for sarcopenia. Resistance exercise training is the most effective method for improving muscle mass and function in older adults. Evidence indicates that resistance training‐induced improvements in muscle mass, strength and function may be further augmented by certain nutrients and nutritional strategies. Ageing is associated with a reduction in the anabolic sensitivity of skeletal muscle to dietary protein ingestion and accumulating evidence indicates that older adults require protein intakes 50%–100% higher than the recommended daily allowance (0.8 g/kg/day) to preserve muscle mass and function. Protein quality, the pattern of protein intake over the day (i.e. per‐meal protein), specific amino acids (i.e. leucine) and other nutrients (i.e. vitamin D, long‐chain n‐3 polyunsaturated fatty acids) are also key considerations. From the personalised nutrition perspective, it is now acknowledged that individual responses to nutrition/exercise interventions are highly variable, despite equivalent compliance, thus highlighting the inadequacy of a ‘one‐size‐fits‐all’ approach. The application of personalised medicine to sarcopenia represents an exciting emerging field of research with the potential to dramatically improve patient outcomes. This approach makes use of recent developments in ‘omics’ technologies and aims to identify the factors (i.e. genes, key biomarkers, medical history, environment, lifestyle) that determine whether an individual is a higher or a lower responder to a particular intervention. This narrative review discusses current evidence regarding nutrition and exercise countermeasures for sarcopenia, with a specific emphasis on recent developments in personalised approaches.
Emergency cricothyroidotomy is a potentially life-saving procedure in the ‘cannot intubate cannot ventilate (CICV)’ scenario. Although surgical cricothyroidotomy remains the technique recommended in ...many ‘CICV’ algorithms, the insertion of a tracheostomy as a cannula over a trocar, or using the Seldinger method, may have advantages as they are more familiar to the anaesthetist. We compared the utility of three cuffed cricothyroidotomy devices: cuffed Melker®, Quicktrach 2®, and PCK® devices, with surgical cricothyroidotomy.
After ethical committee approval and written informed consent, 20 anaesthetists performed cricothyroidotomy with all four devices in random order, in a pig larynx and trachea model covered in cured pelt. The primary endpoints were the rate of successful placement of the cricothyroidotomy device into the trachea and the duration of the insertion attempt.
The Melker® and Quicktrach 2® devices possessed advantages over the surgical approach, in contrast to the PCK® device, which performed less well. All 20 participants inserted the Melker®, with 19 being successful using the surgical approach and the Quicktrach 2®, whereas only 12 successfully inserted the PCK® device (PCK®vs surgical, P=0.02). The Quicktrach 2® had the fastest insertion times and caused least trauma to the posterior tracheal wall. The Melker® was rated highest by the participants and was the only device rated higher than the surgical technique.
The Melker® and Quicktrach 2® devices appear to hold particular promise as alternatives to surgical cricothyroidotomy. Further studies, in more clinically relevant models, are required to confirm these initial positive findings.
Summary
Background
Occupational hand dermatitis poses a serious risk for nurses.
Objectives
To evaluate the clinical and cost‐effectiveness of a complex intervention in reducing the prevalence of ...hand dermatitis in nurses
Methods
This was a cluster randomized controlled trial conducted at 35 hospital trusts, health boards or universities in the UK. Participants were (i) first‐year student nurses with a history of atopic conditions or (ii) intensive care unit (ICU) nurses. Participants at intervention sites received access to a behavioural change programme plus moisturizing creams. Participants at control sites received usual care. The primary outcome was the change of prevalent dermatitis at follow‐up (adjusted for baseline dermatitis) in the intervention vs. the control group. Randomization was blinded to everyone bar the trials unit to ensure allocation concealment. The trial was registered on the ISRCTN registry: ISRCTN53303171.
Results
Fourteen sites were allocated to the intervention arm and 21 to the control arm. In total 2040 (69·5%) nurses consented to participate and were included in the intention‐to‐treat analysis. The baseline questionnaire was completed by 1727 (84·7%) participants. Overall, 789 (91·6%) ICU nurses and 938 (84·0%) student nurses returned completed questionnaires. Of these, 994 (57·6%) had photographs taken at baseline and follow‐up (12–15 months). When adjusted for baseline prevalence of dermatitis and follow‐up interval, the odds ratios (95% confidence intervals) for hand dermatitis at follow‐up in the intervention group relative to the controls were 0·72 (0·33–1·55) and 0·62 (0·35–1·10) for student and ICU nurses, respectively. No harms were reported.
Conclusions
There was insufficient evidence to conclude whether our intervention was effective in reducing hand dermatitis in our populations.
Linked Comment: Brans. Br J Dermatol 2020; 183:411–412.
What is already known about this topics?
Nurses are at high risk of developing hand dermatitis.
Educational interventions are only partially successful in preventing hand dermatitis in healthcare workers.
What does this study add?
The nurse participants in our study had a high level of positive beliefs about good hand care; however, this was not translated sufficiently into their behaviours even when they were provided with access to a behavioural change programme and given ready access to hand moisturizers.
The behavioural change programme intervention did not have a significant effect on reducing hand dermatitis among at‐risk nurses.
Linked Comment: Brans. Br J Dermatol 2020; 183:411–412.
Plain language summary available online
It is well accepted that daily protein intake is an important dietary consideration to limit and treat age-related declines in muscle mass, strength, and function. Furthermore, we propose that there ...is a growing appreciation for the need to consider protein intake on a per-meal basis rather than simply focusing on the total daily protein intake. The existence of a saturable dose-response relationship between muscle protein synthesis (MPS) and the quantity of protein consumed in a single meal/bolus provides the rationale for promoting an even/balanced pattern of daily protein intake. We hypothesize that a balanced/even protein intake pattern with the ingestion a quantity of protein shown to optimally stimulate MPS at each meal may be an effective strategy to alleviate sarcopenic muscle loss. In this review we examine the available evidence supporting the influence of dietary protein intake pattern on muscle protein turnover, muscle mass, and muscle function. We present several practical considerations that, it is proposed, should be taken into account when translating a per-meal protein recommendation into dietary advice for older adults.
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