Functional Laryngeal Assessment in Patients with Tracheostomy Following COVID-19 a Prospective Cohort Study.

To explore laryngeal function of tracheostomised patients with COVID-19 in the acute phase, to identify ways teams may facilitate and expedite tracheostomy weaning and rehabilitation of upper airway function. Consecutive tracheostomised patients underwent laryngeal examination during mechanical ventilation weaning. Primary outcomes included prevalence of upper aerodigestive oedema and airway protection during swallow, tracheostomy duration, ICU frailty scores, and oral intake type. Analyses included bivariate associations and exploratory multivariable regressions. 48 consecutive patients who underwent tracheostomy insertion as part of their respiratory wean following invasive ventilation in a single UK tertiary hospital were included. 21 (43.8%) had impaired airway protection on swallow (PAS ≥ 3) with 32 (66.7%) having marked airway oedema in at least one laryngeal area. Impaired airway protection was associated with longer total artificial airway duration (p = 0.008), longer tracheostomy tube duration (p = 0.007), multiple intubations (p = 0.006) and was associated with persistent ICU acquired weakness at ICU discharge (p = 0.03). Impaired airway protection was also an independent predictor for longer tracheostomy tube duration (p = 0.02, Beta 0.38, 95% CI 2.36 to 27.16). The majority of our study patients presented with complex laryngeal findings which were associated with impaired airway protection. We suggest a proactive standardized scoring and review protocol to manage this complex group of patients in order to maximize health outcomes and ICU resources. Early laryngeal assessment may facilitate weaning from invasive mechanical ventilation and liberation from tracheostomy, as well as practical and objective risk stratification for patients regarding decannulation and feeding.

A new direction for tackling phosphorus inefficiency in the UK food system.

The UK food system is reliant on imported phosphorus (P) to meet food production demand, though inefficient use and poor stewardship means P is currently accumulating in agricultural soils, wasted or lost with detrimental impacts on aquatic environments. This study presents the results of a detailed P Substance Flow Analysis for the UK food system in 2018, developed in collaboration with industry and government, with the key objective of highlighting priority areas for system interventions to improve the sustainability and resilience of P use in the UK food system. In 2018 the UK food system imported 174.6 Gg P, producing food and exportable commodities containing 74.3 Gg P, a P efficiency of only 43%. Three key system hotspots for P inefficiency were identified: Agricultural soil surplus and accumulation (89.2 Gg P), loss to aquatic environments (26.2 Gg P), and waste disposal to landfill and construction (21.8 Gg P). Greatest soil P accumulation occurred in grassland agriculture (85% of total accumulation), driven by loadings of livestock manures. Waste water treatment (12.5 Gg P) and agriculture (8.38 Gg P) account for most P lost to water, and incineration ashes from food system waste (20.3 Gg P) accounted for nearly all P lost to landfill and construction. New strategies and policy to improve the handling and recovery of P from manures, biosolids and food system waste are therefore necessary to improve system P efficiency and reduce P accumulation and losses, though critically, only if they effectively replace imported mineral P fertilisers.

The feasibility of home monitoring of young people with cystic fibrosis: Results from CLIMB-CF.

BACKGROUND: CF is traditionally assessed in clinic. It is unclear if home monitoring of young people with CF is feasible or acceptable. The COVID-19 pandemic has made home monitoring more of a necessity. We report the results of CLIMB-CF, exploring home monitoring's feasibility and potential obstacles. METHODS: We designed a mobile app and enrolled participants with CF aged 2-17 years and their parents for six months. They were asked to complete a variety of measures either daily or twice a week. During the study, participants and their parents completed questionnaires exploring depression, anxiety and quality of life. At the end of the study parents and participants completed acceptability questionnaires. RESULTS: 148 participants were recruited, 4 withdrew prior to starting the study. 82 participants were female with median (IQR) age 7.9 (5.2-12 years). Median data completeness was 40.1% (13.6-69.9%) for the whole cohort; when assessed by age participants aged ≥ 12 years contributed significantly less (15.6% [9.8-30%]). Data completeness decreased over time. There was no significant difference between parental depression and anxiety scores at the start and the end of the study nor in CFQ-R respiratory domain scores for participants ≥ 14 years. The majority of participants did not feel the introduction of home monitoring impacted their daily lives. CONCLUSIONS: Most participants felt home monitoring did not negatively impact their lives and it did not increase depression, anxiety or decrease quality of life. However, uptake was variable, and not well sustained. The teenage years pose a particular challenge and further work is required.

Editorial: Subclinical Psychopathology and the Developing Brain.

Adolescence is an important developmental window, characterized by critical changes in brain development (eg cortical thinning), and also by the peak time of onset for many mental health disorders.1 Understanding the neurodevelopmental roots of psychopathology has been a major focus in our field. Researchers have been charged with providing the foundational knowledge needed to guide the design of effective, neurobiologically based prevention and early intervention efforts.2 Although we have made some gains, we still have far to go. The questions that need to be answered require large-scale, longitudinal studies examining brain development beginning early in life, prior to the onset of mental health disorders, with repeated, multi-level assessments to understand the intertwining cascade of alterations in brain, behavior, and experience over time.

A highly selective pyridoxal-based chemosensor for the detection of Zn(ii) and application in live-cell imaging; X-ray crystallography of pyridoxal-TRIS Schiff-base Zn(ii) and Cu(ii) complexes.

In a simple, one-step reaction, we have synthesized a pyridoxal-based chemosensor by reacting tris(hydroxymethyl)aminomethane (TRIS) together with pyridoxal hydrochloride to yield a Schiff-base ligand that is highly selective for the detection of Zn(ii) ion. Both the ligand and the Zn(ii) complex have been characterized by 1H & 13C NMR, ESI-MS, CHN analyses, and X-ray crystallography. The optical properties of the synthesized ligand were investigated in an aqueous buffer solution and found to be highly selective and sensitive toward Zn(ii) ion through a fluorescence turn-on response. The competition studies reveal the response for zinc ion is unaffected by all alkali and alkaline earth metals; and suppressed by Cu(ii) ion. The ligand itself shows a weak fluorescence intensity (quantum yield, Φ = 0.04), and the addition of zinc ion enhanced the fluorescence intensity 12-fold (quantum yield, Φ = 0.48). The detection limit for zinc ion was 2.77 × 10-8 M, which is significantly lower than the WHO's guideline (76.5 µM). Addition of EDTA to a solution containing the ligand-Zn(ii) complex quenched the fluorescence, indicating the reversibility of Zn(ii) binding. Stoichiometric studies indicated the formation of a 2 : 1 L2Zn complex with a binding constant of 1.2 × 109 M-2 (±25%). The crystal structure of the zinc complex shows the same hydrated L2Zn complex, with Zn(ii) ion binding with an octahedral coordination geometry. We also synthesized the copper(ii) complex of the ligand, and the crystal structure showed the formation of a 1 : 1 adduct, revealing 1-dimensional polymeric networks with octahedral coordinated Cu(ii). The ligand was employed as a sensor to detect zinc ion in HEK293 cell lines derived from human embryonic kidney cells grown in tissue culture which showed strong luminescence in the presence of Zn(ii). We believe that the outstanding turn-on response, sensitivity, selectivity, lower detection limit, and reversibility toward zinc ion will find further application in chemical and biological science.

Sinecatechins ointment as a potential novel treatment for usual type vulval intraepithelial neoplasia: a single-centre double-blind randomised control study.

OBJECTIVE: To compare the safety and efficacy of 10% sinecatechins (Veregen® ) ointment against placebo in the treatment of usual type vulvar intraepithelial neoplasia (uVIN). DESIGN: A Phase II double-blind randomised control trial. SETTING: A tertiary gynaecological oncology referral centre. POPULATION: All women diagnosed with primary and recurrent uVIN. METHODS: Eligible patients were randomised 1:1 to receive either sinecatechins or placebo ointment (applied three times daily for 16 weeks) and were followed up at 2, 4, 8, 16, 32 and 52 weeks. MAIN OUTCOME MEASURES: The primary outcome measure, recorded at 16 and 32 weeks, was histological response (HR). Secondary outcome measures included clinical (CR) response, toxicity, quality of life and pain scores. RESULTS: There was no observed difference in HR between the two arms. However, of the 26 patients who were randomised, all 13 patients who received sinecatechins showed either complete (n = 5) or partial (n = 8) CR, when best CR was evaluated. In placebo group, three patients had complete CR, two had partial CR, six had stable disease and two were lost to follow up. Patients in the sinecatechins group showed a statistically significant improvement in best observed CR as compared with the placebo group (P = 0.002). There was no difference in toxicity reported in either group. CONCLUSION: Although we did not observe a difference in HR between the two treatment arms, we found that 10% sinecatechins application is safe and shows promise in inducing clinical resolution of uVIN lesions and symptom improvement, thus warranting further investigation in a larger multicentre study. TWEETABLE ABSTRACT: A randomised control study indicating that sinecatechins ointment may be a novel treatment for uVIN.

Dysphagia presentation and management following COVID-19: an acute care tertiary centre experience.

OBJECTIVES: As the pathophysiology of COVID-19 emerges, this paper describes dysphagia as a sequela of the disease, including its diagnosis and management, hypothesised causes, symptomatology in relation to viral progression, and concurrent variables such as intubation, tracheostomy and delirium, at a tertiary UK hospital. RESULTS: During the first wave of the COVID-19 pandemic, 208 out of 736 patients (28.9 per cent) admitted to our institution with SARS-CoV-2 were referred for swallow assessment. Of the 208 patients, 102 were admitted to the intensive treatment unit for mechanical ventilation support, of which 82 were tracheostomised. The majority of patients regained near normal swallow function prior to discharge, regardless of intubation duration or tracheostomy status. CONCLUSION: Dysphagia is prevalent in patients admitted either to the intensive treatment unit or the ward with COVID-19 related respiratory issues. This paper describes the crucial role of intensive swallow rehabilitation to manage dysphagia associated with this disease, including therapeutic respiratory weaning for those with a tracheostomy.

Recovery of hematocrit and fat deposits varies by cage size in food-restricted captive red crossbills (Loxia curvirostra).

Hematocrit-or the percent volume of red blood cells in whole blood-is thought to fluctuate adaptively in response to changing oxygen demands that occur during different life activities and in different environments. Because red blood cells are made from materials that can be limiting, however, it is thought that hematocrit may also reflect general body condition and access to resources. We tested the effect of hydration state, resource restriction (i.e., time available to forage), and activity (i.e., different cage sizes) on hematocrit in captive red crossbills (Loxia curvirostra). We found no evidence that a mild dehydration protocol impacts hematocrit and only weak support that mild food restriction impacts hematocrit. Food restriction did, however, reduce fat deposits and fat loss was more significant in birds that were also sampled for hematocrit. Furthermore, food-restricted birds housed in flight aviaries recovered hematocrit but not fat stores following repeated blood sampling, whereas birds housed in small cages lost additional hematocrit but mitigated fat loss following successive bleeds. Together these results suggest that different flight demands may determine response to blood loss during food restriction, potentially revealing a trade-off between fat storage and red blood cell development. Our results also demonstrate the need for scientists to carefully record hematocrit data and the time course across which multiple tubes of blood are collected to avoid confounding real patterns with variation generated by sampling protocol.

Pigmentary keratitis in pugs in the United Kingdom: prevalence and associated features.

BACKGROUND: Pigmentary keratitis (PK) is commonly recognised in Pugs, but its aetiology is not completely understood. The aim of this study was to determine the prevalence and associated features of PK in Pugs in the United Kingdom (UK). RESULTS: A total of 210 Pugs (420 eyes) were recruited from 12 UK dog shows and social events. The median age of Pugs recruited was 2.50 years (range 0.25-16.25 years). Pigmentary keratitis was detected in 369/420 (87.8%) eyes and in at least one eye 193/210 (91.9%) Pugs, of which 17/193 (8.8%) were affected unilaterally and 176/193 (91.2%) bilaterally. Pigmentary keratitis was typically mild to moderate (46.3 and 49.9% of eyes, respectively). Detection of PK was significantly associated with increased age (P = 0.002) and the presence of medial entropion of the lower eyelid (MELE) (P = 0.001). Severity of PK was significantly associated with the grade of MELE (P < 0.001). There was also a correlation between the presence of limbal pigment and PK (P = 0.036) that warrants further study. CONCLUSIONS: This study estimated a high disease prevalence of PK in UK Pugs, and demonstrated significant associations with age and the presence of MELE. These associations, which have not been previously reported, offer an insight into the underlying pathophysiology of this condition in Pugs. The results encourage further population research, such as prospective longitudinal studies. These findings also support the development of clinical and breeding strategies based on the reduction of MELE and, possibly, limbal pigment.

Optimization of Time- and Code-Division-Multiplexed Readout for Athena X-IFU.

Readout of a large, spacecraft-based array of superconducting transition-edge sensors (TESs) requires careful management of the layout area and power dissipation of the cryogenic-circuit components. We present three optimizations of our time- (TDM) and code-division-multiplexing (CDM) systems for the X-ray Integral Field Unit (X-IFU), a several-thousand-pixel-TES array for the planned Athena-satellite mission. The first optimization is a new readout scheme that is a hybrid of CDM and TDM. This C/TDM architecture balances CDM's noise advantage with TDM's layout compactness. The second is a redesign of a component: the shunt resistor that provides a dc-voltage bias to the TESs. A new layout and a thicker Pd-Au resistive layer combine to reduce this resistor's area by more than a factor of 5. Third, we have studied the power dissipated by the first-stage SQUIDs (superconducting quantum-interference devices) and the readout noise versus the critical current of the first-stage SqUIDs. As a result, the X-IFU TDM and C/TDM SQUIDs will have a specified junction critical current of 5 µA. Based on these design optimizations and TDM experiments described by Durkin, et al. (these proceedings), TDM meets all requirements to be X-IFU's backup-readout option. Hybrid C/TDM is another viable option that could save spacecraft resources.

Demonstration of Athena X-IFU Compatible 40-Row Time-Division-Multiplexed Readout.

Time-division multiplexing (TDM) is the backup readout technology for the X-ray Integral Field Unit (X-IFU), a 3,168-pixel X-ray transition-edge sensor (TES) array that will provide imaging spectroscopy for ESA's Athena satellite mission. X-0IFU design studies are considering readout with a multiplexing factor of up to 40. We present data showing 40-row TDM readout (32 TES rows + 8 repeats of the last row) of TESs that are of the same type as those being planned for X-IFU, using measurement and analysis parameters within the ranges specified for X-IFU. Singlecolumn TDM measurements have best-fit energy resolution of (1.91 ± 0.01) eV for the Al Kα complex (1.5 keV), (2.10 ± 0.02) eV for Ti Kα (4.5 keV), (2.23 ± 0.02) eV for Mn Kα (5.9 keV), (2.40 ± 0.02) eV for Co Kα (6.9 keV), and (3.44 ± 0.04) eV for Br Kα (11.9 keV). Three-column measurements have best-fit resolution of (2.03 ± 0.01) eV for Ti Kα and (2.40 ± 0.01) eV for Co Kα. The degradation due to the multiplexed readout ranges from 0.1 eV at the lower end of the energy range to 0.5 eV at the higher end. The demonstrated performance meets X-IFU's energy-resolution and energy-range requirements. True 40-row TDM readout, without repeated rows, of kilopixel scale arrays of X-IFU-like TESs is now under development.

The natural history of classic galactosemia: lessons from the GalNet registry.

BACKGROUND: Classic galactosemia is a rare inborn error of carbohydrate metabolism, caused by a severe deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). A galactose-restricted diet has proven to be very effective to treat the neonatal life-threatening manifestations and has been the cornerstone of treatment for this severe disease. However, burdensome complications occur despite a lifelong diet. For rare diseases, a patient disease specific registry is fundamental to monitor the lifespan pathology and to evaluate the safety and efficacy of potential therapies. In 2014, the international Galactosemias Network (GalNet) developed a web-based patient registry for this disease, the GalNet Registry. The aim was to delineate the natural history of classic galactosemia based on a large dataset of patients. METHODS: Observational data derived from 15 countries and 32 centers including 509 patients were acquired between December 2014 and July 2018. RESULTS: Most affected patients experienced neonatal manifestations (79.8%) and despite following a diet developed brain impairments (85.0%), primary ovarian insufficiency (79.7%) and a diminished bone mineral density (26.5%). Newborn screening, age at onset of dietary treatment, strictness of the galactose-restricted diet, p.Gln188Arg mutation and GALT enzyme activity influenced the clinical picture. Detection by newborn screening and commencement of diet in the first week of life were associated with a more favorable outcome. A homozygous p.Gln188Arg mutation, GALT enzyme activity of ≤ 1% and strict galactose restriction were associated with a less favorable outcome. CONCLUSION: This study describes the natural history of classic galactosemia based on the hitherto largest data set.

Rehabilitation following open partial laryngeal surgery: key issues and recommendations from the UK evidence based meeting on laryngeal cancer.

BACKGROUND: It is recognised that a limited cohort of patients receive open partial laryngeal surgery in specific centres within the UK, so sharing information around key clinical issues and recommendations for practice is necessary to improve outcomes. METHODS: This position statement provides practice recommendations based on a synthesis of the available evidence presented at the 12th Evidence Based Management day on 'Laryngeal Cancer' and the ensuing discussions. Literature searches and critical analysis of available evidence were undertaken and triangulated with the clinical experience of the authors to develop these recommendations.Results and conclusionThis paper presents a comprehensive overview of challenges that the multidisciplinary team may encounter. It provides recommendations for swallow and speech rehabilitation after open partial laryngectomy, and suggests practical ways that these issues may be addressed pre- and post-operatively.

Significant polyp and early colorectal cancer - SPECC: The role of the Colorectal Cancer Clinical Nurse Specialist (CNS): promoting patient-centred care.

AIMS: The colorectal Clinical Nurse Specialist (CNS) makes an important contribution to the care of individuals diagnosed with a significant polyp and early colorectal cancer (SPECC). METHODS: This paper offers an expert opinion on the role of the CNS in SPECC, informed by relevant literature. RESULTS: A CNS can support the patient through the diagnostic and treatment pathway acting as the patient's advocate as a core member of the multidisciplinary team. They will offer support and information to help patients understand their diagnosis, make choices about their available treatment options and help them to feel prepared for any treatment undertaken. CONCLUSION: By providing care that is respectful of, and responsive to, individual patient preferences, needs and values, the CNS can play an important role in promoting patient-centred care.

Association between pregnant women's experience of stress and partners' fly-in-fly-out work.

BACKGROUND: It is relatively common in Western Australia for men to commute long distances and work away from home for extended periods of time, often referred to as fly-in-fly-out work. Women are particularly susceptible to the effects of stress during pregnancy, and the absence of a partner due to working away could be an additional risk to their wellbeing. While there is little published fly-in-fly-out literature, there is evidence that working non-standard hours, more generally, has a negative impact on health and well-being of workers and their families. AIM: To determine if there is an association between pregnant women's report of stress and their partners working fly-in-fly-out, and if so, is there is a differential impact that is dependent on family socioeconomic status. METHODS: Data from a Western Australian pregnancy cohort study were analysed (n=394 families). Couples completed self-report ratings of anxiety, depression, stress, family functioning, and stressful life events. Comparisons were made between three groups: fly-in-fly-out workers, non-fly-in-fly-out regular schedule workers, and non-fly-in-fly-out irregular schedule workers. RESULTS: After controlling for a range of variables, women's stress was significantly associated (p<.05) with their partners working fly-in-fly-out. Neither women's education, partners' occupation nor an interaction between partners' fly-in-fly-out work and partners' occupation were significantly associated with women's stress. CONCLUSION: There is some evidence that the pregnant partners of fly-in-fly-out workers perceive their lives to be more stressful than women whose partner works non-fly-in-fly-out regular schedules.

Evidence for causal top-down frontal contributions to predictive processes in speech perception.

Perception relies on the integration of sensory information and prior expectations. Here we show that selective neurodegeneration of human frontal speech regions results in delayed reconciliation of predictions in temporal cortex. These temporal regions were not atrophic, displayed normal evoked magnetic and electrical power, and preserved neural sensitivity to manipulations of sensory detail. Frontal neurodegeneration does not prevent the perceptual effects of contextual information; instead, prior expectations are applied inflexibly. The precision of predictions correlates with beta power, in line with theoretical models of the neural instantiation of predictive coding. Fronto-temporal interactions are enhanced while participants reconcile prior predictions with degraded sensory signals. Excessively precise predictions can explain several challenging phenomena in frontal aphasias, including agrammatism and subjective difficulties with speech perception. This work demonstrates that higher-level frontal mechanisms for cognitive and behavioural flexibility make a causal functional contribution to the hierarchical generative models underlying speech perception.

The influence of hydroalcoholic media on the performance of Grewia polysaccharide in sustained release tablets.

Co-administration of drugs with alcohol can affect the plasma concentration of drugs in patients. It is also known that the excipients used in the formulation of drugs may not always be resistant to alcohol. This study evaluates effect of varying alcohol concentrations on theophylline release from two grades of Grewia mollis polysaccharides. X-ray microtomography showed that native polysaccharide formulation compacts were not homogenous after the mixing process resulting in its failure in swelling studies. Removal of starch from the native polysaccharide resulted in homogenous formulation compacts resistant to damage in high alcoholic media in pH 6.8 (40%v/v absolute ethanol). Destarched polymer compacts had a significantly higher hardness (375N) than that of the native polysaccharide (82N) and HPMC K4M (146N). Dissolution studies showed similarity at all levels of alcohol tested (f2=57-91) in simulated gastric media (pH 1.2). The dissolution profiles in the simulated intestinal fluids were also similar (f2=60-94), with the exception of the native polysaccharide in pH 6.8 (40%v/v absolute ethanol) (f2=43). This work highlights the properties of Grewia polysaccharide as a matrix former that can resist high alcoholic effects therefore; it may be suitable as an alternative to some of the commercially available matrix formers with wider applications for drug delivery as a cheaper alternative in the developing world.

Intra- and inter-observer reproducibility of CINtec® PLUS in ThinPrep® cytology preparations.

BACKGROUND: This study evaluated the intra- and inter-observer reproducibility of the dual-stain biomarker, CINtec® PLUS cytology in ThinPrep® specimens, for improved specificity in the detection of cervical disease in women testing human papillomavirus (HPV) positive. METHODS: A total of 972 cases of HPV-positive women from a triage and primary HPV screening population were selected from an ongoing study evaluating the clinical performance of CINtec® PLUS cytology. For reproducibility analyses, three cytotechnologists rescreened sets of slides which they had previously reported themselves and which were previously reported by each of the other cytotechnologists. The original results of slides previously screened by each of the three cytotechnologists were also compared with the results of an expert reference evaluator. RESULTS: Intra- and inter-observer agreement for paired evaluations between reviewers ranged from 82.8% to 94.9% (kappa 0.65-0.91) and 89.2% to 93% (kappa 0.83-0.88), respectively. Reproducibility analyses between the cytotechnologists and the reference evaluator revealed agreements ranging from 95.5% to 98% (kappa 0.89-0.96). CONCLUSION: Evaluation of the dual-stain biomarker showed a high level of agreement across all evaluators suggesting that CINtec® PLUS cytology will perform well in the hands of cytotechnologists and pathologist reviewers and could be introduced into cellular pathology laboratories that employ ThinPrep® LBC with a minimum effort.

Current insights into the aetiology, pathobiology, and management of local disease recurrence in squamous cell carcinoma of the vulva.

Squamous cell carcinoma of the vulva is predominantly a disease of the elderly, where the mainstay of treatment is radical surgery. Local vulval recurrence (LVR) is a significant problem for these patients, and the rates of recurrence have not improved over the last three decades. Disappointingly, we still lack an understanding of how LVRs develop, and the best approach to prevent and manage the condition. This review discusses recent insights into the key prognostic factors that influence the risk of recurrence, focusing on the role of tumour-adjacent non-neoplastic epithelial disorders, which are thought to play a causative role. TWEETABLE ABSTRACT: A review that discusses the key prognostic factors that influence local recurrence in vulval cancer.