State-level trends in the greenhouse gas emission intensity of US milk production.

The greenhouse gas emission intensity of US milk production (i.e., greenhouse gas emissions per unit of production) has varied across time and states. However, research has not examined how farm-sector trends affect the state-level emission intensity of production. We estimated fixed effects regressions with state-level panel data from 1992 through 2017 to test how US dairy farm-sector changes influenced the greenhouse gas emission intensity of production. We found that increases in per cow milk productivity reduced the enteric greenhouse gas emission intensity of milk production, while it had no statistically significant effect on the manure greenhouse gas emission intensity of production. In contrast, increases in average farm size and the number of farms reduced the manure greenhouse gas emission intensity of milk production, while they did not affect the enteric greenhouse gas emission intensity of production.

How applicable is the TNM 8 staging for human papillomavirus (HPV) related oropharyngeal squamous cell carcinoma (OPSCC) to a UK population of 106 patients? : A cohort comparison of the TNM 7 and TNM8 staging systems for HPV positive oropharyngeal cancer in a UK population.

PURPOSE: TNM8 introduced a new staging system for HPV positive oropharyngeal squamous cell carcinoma (OPSCC). This study aimed to investigate whether the changes made in TNM8 offer the perceived benefit in prognostication when compared to TNM7 in a specific patient population in the North East of England. METHODS: A retrospective cohort comparison study of all patients with HPV positive OPSCC (n = 106) through the Newcastle Head and Neck MDT between January 2012 to December 2014. Overall survival (OS) and Disease specific survival (DSS) data at 3 years was gathered for both TNM7 and TNM8. Log rank test was used to compare survival curves. Harrell's C-index adjusted for age and smoking status was used to assess prognostic ability of the two staging methods. RESULTS: TNM8 downstages disease (TNM7 stage IV patients n = 74, TNM8 stage IV patients n = 2) but gives a more even distribution of patients across disease stages. Survival for TNM8 stage II and III is similar. In our small cohort, the log-rank test detected differences in OS between stages for both scoring methods (TNM7 p = 0.006, TNM8 p < 0.001) and similarly for DSS (TNM7 p = 0.001, TNM8 p < 0.001). Harrell's C-index was similar for both models for OS (TNM7 0.71, TNM8 0.71) and DSS (TNM7 0.74, TNM8 0.70). CONCLUSION: TNM8 downstages disease and prognosticates well for stage I disease but does not differentiate between stage II and III disease when compared to TNM7. Further adaptation is required to address this to make TNM8 a more accurate prognostic tool.

Does the gene matter? Genotype-phenotype and genotype-outcome associations in congenital melanocytic naevi.

BACKGROUND: Genotype-phenotype studies can identify subgroups of patients with specific clinical features or differing outcomes, which can help shape management. OBJECTIVES: To characterize the frequency of different causative genotypes in congenital melanocytic naevi (CMN), and to investigate genotype-phenotype and genotype-outcome associations. METHODS: We conducted a large cohort study in which we undertook MC1R genotyping from blood, and high-sensitivity genotyping of NRAS and BRAF hotspots in 156 naevus biopsies from 134 patients with CMN [male 40%; multiple CMN 76%; projected adult size (PAS) > 20 cm, 59%]. RESULTS: Mosaic NRAS mutations were detected in 68%, mutually exclusive with BRAF mutations in 7%, with double wild-type in 25%. Two separate naevi were sequenced in five of seven patients with BRAF mutations, confirming clonality. Five of seven patients with BRAF mutations had a dramatic multinodular phenotype, with characteristic histology distinct from classical proliferative nodules. NRAS mutation was the commonest in all sizes of CMN, but was particularly common in naevi with PAS > 60 cm, implying more tolerance to that mutation early in embryogenesis. Facial features were less common in double wild-type patients. Importantly, the incidence of congenital neurological disease, and apparently of melanoma, was not altered by genotype; no cases of melanoma were seen in BRAF-mutant multiple CMN, however, this genotype is rare. CONCLUSIONS: CMN of all sizes are most commonly caused by mutations in NRAS. BRAF is confirmed as a much rarer cause of multiple CMN, and appears to be commonly associated with a multinodular phenotype. Genotype in this cohort was not associated with differences in incidence of neurological disease in childhood. However, genotyping should be undertaken in suspected melanoma, for guidance of treatment. What's already known about this topic? Multiple congenital melanocytic naevi (CMN) have been shown to be caused by NRAS mosaic mutations in 70-80% of cases, by BRAF mosaicism in one case report and by inference in some previous cases. There has been debate about genotypic association with different sizes of CMN, and no data on genotype-outcome. What does this study add? NRAS mosaicism was found in 68%, BRAF in 7% and double wild-type in 25% of cases of CMN. NRAS was the commonest mutation in all sizes of CMN, but was nearly universal in projected adult size > 60 cm. BRAF is often associated with a distinct multinodular clinical/histological phenotype. Adverse outcomes did not differ between genotypes on current numbers.

Cetuximab in the management of nasopharyngeal carcinoma - a narrative review.

BACKGROUND: Concurrent chemotherapy with radiotherapy is the standard treatment for locoregionally advanced nasopharyngeal cancer. Cetuximab can be used in the treatment of head and neck squamous cell carcinoma. However, the randomised studies that led to approval for its use in this setting excluded nasopharyngeal cancer. In the context of limited data for the use of cetuximab in nasopharyngeal cancer in the medical literature, this review aimed to summarise the current evidence for its use in both primary and recurrent or metastatic disease. METHOD: A literature search was performed using the keywords 'nasopharyngeal neoplasm', 'cetuximab' and 'Erbitux'. RESULTS: Twenty studies were included. There were no randomised phase III trials, but there were nine phase II trials. The use of cetuximab in the treatment of nasopharyngeal carcinoma has been tested in various settings, including in combination with induction chemotherapy and concurrent chemoradiotherapy, and in the palliative setting. CONCLUSION: There is no evidence of benefit from the addition of cetuximab to standard management protocols, and there is some evidence of increased toxicity. There is more promise for its use in metastatic or locally recurrent settings. This review draws together the existing evidence and could provide a focus for future studies.

Preoperative MR Imaging to Differentiate Chordoid Meningiomas from Other Meningioma Histologic Subtypes.

BACKGROUND AND PURPOSE: Chordoid meningiomas are uncommon WHO grade II primary intracranial neoplasms that possess unique chordoid histology and follow an aggressive clinical course. Our aim was to assess the utility of qualitative MR imaging features and quantitative apparent diffusion coefficient values as distinguishing preoperative MR imaging metrics to identify and differentiate chordoid histology from other meningioma histologic subtypes. MATERIALS AND METHODS: Twenty-one patients with meningiomas with chordoid histology, which included both chordoid meningiomas (>50% chordoid histology) and meningiomas with focal chordoid histology (<50% chordoid histology) with available preoperative MR imaging examinations, including diffusion-weighted imaging, were identified. Qualitative imaging features and quantitative ADC values were compared between meningiomas with chordoid histology and 42 nonchordoid meningiomas (29 WHO grade I, eleven WHO grade II, and 2 WHO grade III). RESULTS: The median ADC (10-3mm2/s) of meningiomas with chordoid histology was significantly higher than nonchordoid meningiomas (1.16 versus 0.92, P < .001), as was the median normalized ADC (1.60 versus 1.19, P < .001). In subgroup analysis, the median and normalized ADC values of chordoid meningiomas (n = 11) were significantly higher than those in meningiomas with focal chordoid histology (n = 10, P < .001 and P < .001, respectively) or nonchordoid meningiomas (n = 42, P < .001 and <0.001, respectively). Median and normalized ADC values were not significantly different between the meningiomas with focal chordoid histology and nonchordoid meningiomas (P = .816 and .301, respectively). Among the qualitative imaging features, only DWI signal intensity was significantly associated with meningiomas with chordoid histology diagnosis. CONCLUSIONS: ADC values are higher in chordoid compared with nonchordoid meningiomas and may be used to discriminate the degree of chordoid histology in meningiomas. While qualitative MR imaging features do not strongly discriminate chordoid from nonchordoid meningiomas, DWI may allow preoperative identification of chordoid meningiomas.

A 24-month cost and outcome analysis comparing traditional fronto-orbital advancment and remodeling with endoscopic strip craniectomy and molding helmet in the management of unicoronal craniosynostosis: A retrospective bi-institutional review.

INTRODUCTION: Endoscopic strip craniectomy with helmeting (ESCH) has been shown to be a safe and efficacious alternative to fronto-orbital remodeling (FOR) for selected children with craniosynostosis. In addition to clinical factors, there may be economic benefits from the use of ESCH instead of FOR. METHODS: A retrospective review of 23 patients with nonsyndromic unicoronal craniosynostosis (UCS) treated with FOR was carried out at Great Ormond Street Hospital (GOSH) for Children in London, UK. Secondary data were used for the ESCH cohort from a paper published by Jimenez and Barone (2013). Data were collected on surgical time, transfusion rates, length of hospital stay, adverse event rates, reintervention rates, and overall costs. Costs were categorized and then assigned to the appropriate data sets. RESULTS: The mean age of patients undergoing FOR (vs. ESCH) was 17.4 mo (vs. 3.1 mo) with a mean surgical time of 234 min (vs. 55 min), mean transfusion volume of 221.6 mL (vs. 80.0 mL), mean transfusion rate of 14/23 (vs. 2/115), and a total immediate overnight stay of 3.13 days (vs. 97% next-day discharge). The FOR group had a higher adverse event rate (5/23 vs. 4/115, p=<0.005) and a higher number requiring extraocular muscle surgery (4/23 vs. 7/109, p=0.16). There was a substantial difference in overall costs between the two groups. Total variance cost for the FOR group was £7436.5 vs. £4951.35, representing a cost difference of £2485.15 over the 24-month study period. CONCLUSION: ESCH, in comparison to FOR, appears as a more economical method in the management of USC patients, as well as having clinical benefits including reduced adverse event rate and improved ophthalmic outcomes.

The effects of acute hypoxia on tissue oxygenation and circulating alarmins in healthy adults.

The binding of high-mobility group box-1 (HMGB-1) to the membrane receptor for advanced glycation end-products (mRAGE) is a key early mediator of non-infectious inflammation and its triggers include ischaemia/hypoxia. The effects of acute hypoxia on soluble RAGE (sRAGE) are unknown. Fourteen healthy adults (50 % women; 26.6+/-3.8 years) were assessed at baseline normoxia (T0), followed by four time-points (T90, 95, 100 and 180 min) over three hours of continuous normobaric hypoxia (NH, 4,450 m equivalent) and again 60 min after return to normoxia (T240). A 5-min exercise step test was performed during NH at T90. Plasma concentrations of HMGB-1, sRAGE VCAM-1, ICAM-1, VEGF IL-8 and IL-13 were measured using venous blood. Arterial and tissue oxygen saturations were measured using pulse oximetry (SpO(2)) and near-infrared spectroscopy (StO(2)), respectively. NH led to a significant reduction in SpO(2), StO(2), sRAGE and VEGF, which was compounded by exercise, before increasing to baseline values with normoxic restoration (T240). NH-exercise led to a paired increase in HMGB-1. sRAGE inversely correlated with HMGB-1 (r=-0.32; p=0.006), heart rate (r=-0.43; p=0.004) but was not linked to SpO(2) or StO(2). In conclusion, short-term NH leads to a fall in sRAGE and VEGF concentrations with a transient rise post NH-exercise in HMGB-1.

General illness and psychological factors in patients with chronic nasal symptoms.

OBJECTIVES: Only a minority of patients referred to specialists with sinonasal symptoms have clear evidence of chronic rhinosinusitis (CRS). This study aims to estimate the prevalence of and associations between (i) general illness factors (fatigue, autonomic dysfunction) and (ii) psychological factors (anxiety, depression, somatisation, personality traits) in patients presenting with sinonasal symptoms. DESIGN: The following validated questionnaires were administered to patients: the Sino-Nasal Outcome Test-22 (SNOT-22) identifying symptom burden, Composite Autonomic Symptom Score-31 (COMPASS-31) measuring autonomic function, Chalder Fatigue Questionnaire, Patient Health Questionnaire-15 (PHQ-15) addressing somatisation symptoms, Hospital Anxiety and Depression Scale (HADS), and the International Personality Item Pool-50 (IPIP-50). Comparisons were made with normative and general population data, and relationships were analysed using nonparametric correlation. SETTING: Secondary care ENT outpatients. PARTICIPANTS: Adults referred with chronic sinonasal symptoms. MAIN OUTCOME MEASURES: SNOT-22, COMPASS-31, Chalder, PHQ-15, HADS, and IPIP-50 questionnaire scores. RESULTS: Sixty-one patients were included. There was a high prevalence of all general and psychological factors assessed compared with controls. Total SNOT-22 scores showed significant correlation with Chalder fatigue scores, total autonomic dysfunction score, anxiety, depression, somatisation tendencies and the emotionally unstable personality trait. Emotional instability and psychological dysfunction correlated significantly with sleep and psychological subscales of SNOT-22 but not the rhinological or ear/facial subscales. CONCLUSION: Patients with sinonasal symptoms demonstrate high prevalence and complex associations of general illness factors, psychological distress and certain personality traits. The SNOT-22 is a valuable tool, but its utility is limited by correlations with these confounding factors (eg psychological factors) that may exaggerate the total score. The use of the SNOT-22 component subscales is likely to provide more clinically meaningful and discriminant information.

The Birmingham Interlocking Pelvic Osteotomy for acetabular dysplasia: 13- to 21-year survival outcomes.

AIMS: The aim of this study was to evaluate the long-term clinical and radiographic outcomes of the Birmingham Interlocking Pelvic Osteotomy (BIPO). PATIENTS AND METHODS: In this prospective study, we report the mid- to long-term clinical outcomes of the first 100 consecutive patients (116 hips; 88 in women, 28 in men) undergoing BIPO, reflecting the surgeon's learning curve. Failure was defined as conversion to hip arthroplasty. The mean age at operation was 31 years (7 to 57). Three patients (three hips) were lost to follow-up. RESULTS: Survivorship was 76% at ten years and 57% at a mean of 17 years. Younger patients (< 20 years) had the best survivorship (20 hips at risk; 90% at 17 years; 95% confidence interval 65 to 97). Post-operative complications occurred after 12 operations (10.4%) over the duration of the study. Increasing patient age and hip arthritis grade were primary determinants of surgical failure. CONCLUSION: BIPO provides good to excellent survivorship in appropriately selected patients, with a relatively low rate of complications. Our results are comparable with other established methods of periacetabular osteotomy (PAO), such as the Bernese PAO, even during the surgeon's initial learning curve. Cite this article: Bone Joint J 2017;99-B:724-31.

Trans-oral robotic assisted tongue base mucosectomy for investigation of cancer of unknown primary in the head and neck region. The UK experience.

OBJECTIVES: The diagnosis of cancer of unknown primary (CUP) in head and neck occurs when the treating clinicians have utilised all available diagnostic tests and failed to identify the origin of the disease. There is no agreed consensus on which diagnostic investigations to use, or the order in which to use them in, although broad recommendations exist. Small tumours arising in the tongue base can be below the limits of resolution of conventional diagnostic techniques. Given the difficulty in targeting the tongue base, current practice involves blind random biopsies, which leads to a variable detection rate. Robotically assisted surgical removal of the tongue base, tongue base mucosectomy (TBM) has been shown to improve diagnostic yield. This study reports the diagnostic hit rate for tongue base primaries using this technique. DESIGN: Retrospective case review. SETTING: UK Head and Neck Centres. PARTICIPANTS: Patients presenting as an unknown primary, investigated with clinical examination, PET-CT and palatine tonsillectomy. MAIN OUTCOME MEASURES: The detection of a primary site of head and neck cancer in the otherwise unknown primary tumour. RESULTS: The primary tumour site was identified in the tongue base in 53% (n=17) of patients. In 15 patients the tumour was in the ipsliateral tongue base (88%) while in two cases (12%) the tumour was located in contra lateral tongue base. CONCLUSIONS: Trans-oral robotic assisted TBM raises the possibility of identifying over 50% of tumours that would otherwise be classified as CUP. Identifying these in the contralateral tongue base has implications for treatment planning and outcome.

'Thinking that somebody's going to delay [a tonsillectomy] for one to two years is quite horrifying really': a qualitative feasibility study for the NAtional Trial of Tonsillectomy IN Adults (NATTINA Part 2).

OBJECTIVES: Level one evidence on the value of adult tonsillectomy versus non-surgical management remains scarce. Before embarking on a costly national randomised controlled trial, it is essential to establish its feasibility. DESIGN: Feasibility study with in-depth qualitative and cognitive interviews. SETTING: ENT staff and patients were recruited from nine hospital centres across England and Scotland. PARTICIPANTS: Patients who were referred for tonsillectomy (n = 15), a convenience sample of general practitioners (n = 11) and ear, nose and throat staff (n = 22). MAIN OUTCOME MEASURES: To ascertain whether ear, nose and throat staff would be willing to randomise patients to the treatment arms. To assess general practitioners' willingness to refer patients to the NAtional Trial of Tonsillectomy IN Adults (NATTINA) centres. To assess patients' willingness to be randomised and the acceptability of the deferred surgery treatment arm. To ascertain whether the study could progress to the pilot trial stage. RESULTS: Ear, nose and throat staff and general practitioners were willing to randomise patients to the proposed NATTINA. Not all ENT staff were in equipoise concerning the treatment pathways. Patients were reluctant to be randomised into the deferred surgery group if they had already waited a substantial time before being referred. CONCLUSIONS: Findings suggest that the NATTINA may not be feasible. Proposed methods could not be realistically assessed without a pilot trial. Due to the importance of the question, as evidenced by NATTINA clinicians, and strong support from ENT staff, the pilot trial proceeded, with modifications.

Baseline swallowing measures predict recovery at 6 weeks after transoral robotic surgery for head and neck cancer.

OBJECTIVES: To explore whether pre-treatment swallowing measures predict swallowing recovery at 6 weeks after transoral robotic surgery (TORS). DESIGN: Prospective cohort study. SETTING: Tertiary care cancer centre in the United Kingdom. PARTICIPANTS: Fifty-one consecutive patients undergoing TORS for head and neck cancer, between April 2013 and February 2015. MAIN OUTCOME MEASURES: Swallowing function assessed by Performance Status Scale (PSS) Normalcy of Diet, timed water swallow test capacity scores (WST) and duration of tube feeding. RESULTS: The primary site distribution was as follows: 21 oropharynx, 8 larynx, 6 mucosectomy and 6 hypopharynx. T stages included 7 staged Tx, 21 T1-T2 tumours and 1 T3 tumour. Moderate-to-severe comorbidity was found in 45/51 patients. Mean PSS score was 83 (sd 27.54); mean WST score was 11.14 (sd 7.97). Most patients (73%) required tube feeding post-operatively, with mean tube feed duration of 18.08 days (sd 17.91); 76% resumed oral intake by 6 weeks. Pre-treatment swallow tests showed moderate negative correlation with tube feeding duration: PSS (rho 0-.430, P = .003); WST (rho 0-.503, P = 0.002). CONCLUSIONS: The majority of TORS patients resume oral intake by 6 weeks. This study shows that impaired swallowing prior to surgery correlates with post-operative duration of tube feeding and strengthens the evidence for the utility of these measures in this clinical setting.

The changing landscape of oropharyngeal cancer management.

BACKGROUND: Oropharyngeal cancer is increasing in prevalence in the UK and this is thought to be due to the emergence of disease related to human papilloma virus. METHOD: A literature review was conducted on the diagnosis and latest management of oropharyngeal cancer. RESULTS: In non-smokers, human papilloma virus related disease is thought to have better outcomes, but this casts doubt on previous research which did not stratify patients according to human papilloma virus status. However, this theory provides a route for researchers to risk stratify and de-escalate treatments, and hence reduce treatment burden. In addition, the emergence of minimally invasive transoral techniques allows surgeons to remove large tumours without many of the side effects associated with radical (chemo)radiotherapy. CONCLUSION: The emergence of human papilloma virus related disease and minimally invasive techniques have led the clinical and academic community to reconsider how oropharyngeal cancer is managed. Comparative and risk-stratification trials are urgently required and ongoing.

Oropharyngeal cancer: United Kingdom National Multidisciplinary Guidelines.

This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. There has been significant debate in the management of oropharyngeal cancer in the last decade, especially in light of the increased incidence, clarity on the role of the human papilloma virus in this disease and the treatment responsiveness of the human papilloma virus positive cancers. This paper discusses the evidence base pertaining to the management of oropharyngeal cancer and provides recommendations on management for this group of patients receiving cancer care. Recommendations • Cross-sectional imaging is required in all cases to complete assessment and staging. (R) • Magnetic resonance imaging is recommended for primary site and computed tomography scan for neck and chest. (R) • Positron emission tomography combined with computed tomography scanning is recommended for the assessment of response after chemoradiotherapy, and has a role in assessing recurrence. (R) • Examination under anaesthetic is strongly recommended, but not mandatory. (R) • Histological diagnosis is mandatory in most cases, especially for patients receiving treatment with curative intent. (R) • Oropharyngeal carcinoma histopathology reports should be prepared according to The Royal College of Pathologists Guidelines. (G) • Human papilloma virus (HPV) testing should be carried out for all oropharyngeal squamous cell carcinomas as recommended in The Royal College of Pathologists Guidelines. (R) • Human papilloma virus testing for oropharyngeal cancer should be performed within a diagnostic service where the laboratory procedures and reporting standards are quality assured. (G) • Treatment options for T1-T2 N0 oropharyngeal squamous cell carcinoma include radical radiotherapy or transoral surgery and neck dissection (with post-operative (chemo)radiotherapy if there are adverse pathological features on histological examination). (R) • Transoral surgery is preferable to open techniques and is associated with good functional outcomes in retrospective series. (R) • If treated surgically, neck dissection should include levels II-IV and possibly level I. Level IIb can be omitted if there is no disease in level IIa. (R) • If treated with radiotherapy, levels II-IV should be included, and possibly level Ib in selected cases. (R) • Altering the modalities of treatment according to HPV status is currently controversial and should be undertaken only in clinical trials. (R) • Where possible, patients should be offered the opportunity to enrol in clinical trials in the field. (G).

Novel Therapy of Hyperhomocysteinemia in Mild Cognitive Impairment, Alzheimer's Disease, and Other Dementing Disorders.

OBJECTIVES: Studies have produced conflicting results assessing hyperhomocysteinemia (HYH) treatment with B vitamins in patients with normal cognition, Alzheimer's disease and related disorders (ADRD). This study examined the effect of HYH management with L-methylfolate (LMF), methylcobalamin (MeCbl; B12), and N-acetyl-cysteine (CFLN: Cerefolin®/Cerefolin-NAC®) on cognitive decline. DESIGN: Prospective, case-control study of subjects followed longitudinally. SETTING: Outpatient clinic for cognitive disorders. PARTICIPANTS: 116 ADRD patients (34 with HYH, 82 with No-HYH) met inclusion and exclusion criteria to participate. No study participant took B vitamins. INTERVENTION: HYH patients received CFLN, and No-HYH patients did not. MEASUREMENTS: Cognitive outcome measures included MCI Screen (memory), CERAD Drawings (constructional praxis), Ishihara Number Naming (object recognition), Trails A and B (executive function), and F-A-S test (verbal fluency). Dependent or predictor measures included demographics, functional severity, CFLN and no CFLN treatment duration, ADRD diagnosis, memantine and cholinesterase inhibitor treatment. Linear mixed effects models with covariate adjustment were used to evaluate rate of change on cognitive outcomes. RESULTS: The duration of CFLN treatment, compared to an equivalent duration without CFLN treatment, significantly slowed decline in learning and memory, constructional praxis, and visual-spatial executive function (Trails B). CFLN treatment slowed cognitive decline significantly more for patients with milder baseline severity. CFLN treatment effect increased as baseline functional severity decreased. The analytical model showed that treatment duration must exceed some minimum period of at least one year to slow the rate of cognitive decline. CONCLUSION: After covariate adjustment, HYH+CFLN significantly slowed cognitive decline compared to No-HYH+No-CFLN. Longer CFLN treatment duration, milder baseline severity, and magnitude of homocysteine reduction from baseline were all significant predictors. There are a number of factors that could account for disagreement with other clinical trials of B vitamin treatment of HYH. Moreover, CFLN is chemically distinct from commonly used B vitamins as both LMF and MeCbl are the fully reduced and bioactive functional forms; CLFN also contains the glutathione precursor, N-acetyl-cysteine. The findings of other B vitamin trials of HYH can, therefore, only partly account for treatment effects of CFLN. These findings warrant further evaluation with a randomized, placebo-controlled trial.