Astrocytes display cell autonomous and diverse early reactive states in familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a rapidly progressive and fatal disease. Although astrocytes are increasingly recognized contributors to the underlying pathogenesis, the cellular autonomy and uniformity of astrocyte reactive transformation in different genetic forms of amyotrophic lateral sclerosis remain unresolved. Here we systematically examine these issues by using highly enriched and human induced pluripotent stem cell-derived astrocytes from patients with VCP and SOD1 mutations. We show that VCP mutant astrocytes undergo cell-autonomous reactive transformation characterized by increased expression of complement component 3 (C3) in addition to several characteristic gene expression changes. We then demonstrate that isochronic SOD1 mutant astrocytes also undergo a cell-autonomous reactive transformation, but that this is molecularly distinct from VCP mutant astrocytes. This is shown through transcriptome-wide analyses, identifying divergent gene expression profiles and activation of different key transcription factors in SOD1 and VCP mutant human induced pluripotent stem cell-derived astrocytes. Finally, we show functional differences in the basal cytokine secretome between VCP and SOD1 mutant human induced pluripotent stem cell-derived astrocytes. Our data therefore reveal that reactive transformation can occur cell autonomously in human amyotrophic lateral sclerosis astrocytes and with a striking degree of early molecular and functional heterogeneity when comparing different disease-causing mutations. These insights may be important when considering astrocyte reactivity as a putative therapeutic target in familial amyotrophic lateral sclerosis.

Efficacy of an experimental 3% potassium nitrate mouthwash in providing long-term relief from dentin hypersensitivity: An 8-week randomized controlled study (Study 2).

PURPOSE: To evaluate the efficacy of an experimental mouthwash containing 3% potassium nitrate (KNO3) in the relief of dentin hypersensitivity when used as an adjunct to brushing with fluoride toothpaste compared with the use of the same toothpaste alone. METHODS: This was a randomized, two-treatment, examiner-blind, parallel-design single-center, 8-week study in healthy subjects with self-reported and clinically diagnosed dentin hypersensitivity. Subjects were randomized to receive either fluoride toothpaste plus 3.0% KNO2 mouthwash or the same fluoride toothpaste alone, and instructed to use their allocated treatment twice daily for the next 8 weeks. Dentin hypersensitivity was evaluated at baseline and following 4 and 8 weeks of treatment through assessment of responses to evaporative (air) and tactile stimuli [measured by the Schiff sensitivity scale/a visual rating scale (VRS) and tactile threshold, respectively], and using the Dentin Hypersensitivity Experience Questionnaire (DHEQ, a validated quality-of-life instrument for dentin hyper-sensitivity). RESULTS: A total of 135 subjects were randomized and all completed the study. Both treatment groups demonstrated statistically significant improvements in sensitivity from baseline for each clinical measure of sensitivity (P< 0.0001) at Week 4 and Week 8. The toothpaste plus mouthwash group showed greater reductions in sensitivity at both timepoints for all clinical measures; between-treatment differences were only statistically significant for responses to an evaporative (air) stimulus (Schiff sensitivity score and VRS) at Week 4. There was evidence of an improvement in dentin hypersensitivity-associated quality of life as measured by changes from baseline in several DHEQ parameters for both treatment groups, but there were no statistically significant differences between treatments. CLINICAL SIGNIFICANCE: Although in the current study adjunctive use of a 3% KNO2 mouthwash did not provide statistically significant improvements in dentin hypersensitivity for all clinical measures at all timepoints compared with use of fluoride toothpaste alone, the reductions in sensitivity observed in this study are compatible with the findings of a previous study that showed adjunctive use of a 3% KNO2 mouthwash to be effective in providing relief from dentin hypersensitivity after 8 weeks' twice-daily use.

Efficacy of an experimental 3% potassium nitrate mouthwash in providing long-term relief from dentin hypersensitivity:An 8-week randomized controlled study (Study 1).

PURPOSE: To evaluate the efficacy of an experimental mouthwash containing 3% potassium nitrate (KNO3) in relieving dentin hypersensitivity when used as an adjunct to brushing with fluoride toothpaste compared with use of the same toothpaste alone. METHODS: This was one of three randomized, two-treatment, examiner-blind, parallel-design, single-site, 8-week studies in healthy subjects with self-reported and clinically diagnosed dentin hypersensitivity. Subjects were randomized to receive either fluoride toothpaste plus 3% KNO3 mouthwash or the same fluoride toothpaste alone, and instructed to use their allocated treatment twice daily for the next 8 weeks. Dentin hypersensitivity was evaluated at baseline and following 4 and 8 weeks of treatment through assessment of responses to evaporative (air) and tactile stimuli [measured by the Schiff Sensitivity Scale, a visual rating scale (VRS), and tactile threshold, respectively], and using the Dentin Hypersensitivity Experience Questionnaire (DHEQ; a validated quality-of-life instrument for dentin hypersensitivity). RESULTS: A total of 216 subjects were randomized and 214 completed the study. Both treatment groups demonstrated statistically significant reductions from baseline for each clinical measure of sensitivity (P≤ 0.01) at Weeks 4 and 8. Use of the 3% KNO3 mouthwash after brushing with fluoride toothpaste resulted in statistically significantly greater reductions in sensitivity to an evaporative (air) stimulus (mean Schiff score and mean VRS, P< 0.001; primary objective mean Schiff score at Week 8, P< 0.0001) and statistically significantly higher tactile threshold (P< 0.001) at Weeks 4 and 8 compared with toothpaste alone. The DHEQ responses reflected the clinical outcomes for several parameters, indicating a significant improvement in oral health-related quality of life after 8 weeks' use of the 3% KNO3 mouthwash. CLINICAL SIGNIFICANCE: The results of this study suggest that daily use of a 3% KNO3 mouthwash as an adjunct to brushing with fluoride toothpaste provides clinically relevant improvements in dentin hypersensitivity after 8 weeks' twice-daily use.

Three randomized clinical trials to assess the short-term efficacy of anhydrous 0.454% w/w stannous fluoride dentifrices for the relief of dentin hypersensitivity.

PURPOSE: To assess the short-term efficacy of dentifrices containing 0.454% weight/weight (w/w) stannous fluoride applied using a focused brushing methodology for the relief of dentin hypersensitivity (DH). METHODS: Three randomized, examiner blind, controlled, two treatment arm, parallel group studies were conducted utilizing a novel application method in which, prior to brushing the whole mouth, the stannous fluoride dentifrice was applied to two sensitive teeth by focused brushing. DH was assessed with an evaporative (air) stimulus (with the Schiff Sensitivity Scale and a Visual Analogue Scale [VAS, Studies 1 and 3 only]) and a tactile stimulus (using a Yeaple Probe). Clinical assessments were made at baseline, immediately after first use of study dentifrice and after 3 and 14 days of twice daily brushing. Study 1 compared a marketed 0.454% w/w stannous fluoride dentifrice indicated for short-term DH relief to a marketed standard fluoride dentifrice (negative control). Studies 2 and 3 compared a novel anhydrous 0.454% w/w stannous fluoride dentifrice to the same negative control. RESULTS: For Studies 1, 2 and 3, 118, 113 and 120 subjects respectively were randomized to treatment and included in the intent-to-treat populations. Study 1 showed significant DH improvements in all measures for the test dentifrice compared to the negative control at Day 14. Study 2 showed significant differences in favor of the test dentifrice for all measures at all time points (Immediate, Days 3 and 14). In Study 3, treatment with both test and control dentifrices resulted in significant improvements over baseline, but there were no significant between-treatment differences. While these studies provide evidence for relief of DH with 0.454% w/w stannous fluoride dentifrices after short-term use (14 days) using a novel focused brushing methodology, the evidence, especially at the earliest time points, is inconclusive and further testing is needed. Study dentifrices were well tolerated. ClinicalTrials.gov trial registration numbers: Study 1 NCT01494649; Study 2: NCT01592851; Study 3: NCT01724008; funded by GSK Consumer Healthcare.

Efficacy of an experimental toothpaste containing 5% calcium sodium phosphosilicate in the relief of dentin hypersensitivity: An 8-week randomized study (Study 1).

PURPOSE: To evaluate the efficacy of an experimental toothpaste containing 5% (w/w) calcium sodium phosphosilicate (CSPS) in relieving dentin hypersensitivity (DH) compared with control toothpastes containing no known anti-sensitivity ingredients. METHODS: This was the first of two exploratory, randomized, four-treatment, examiner-blind, parallel-design, single-site, 8-week studies in healthy subjects with self-reported and clinically diagnosed DH. The experimental toothpaste contained 5% CSPS with a modified surfactant system, developed to enhance its organoleptic properties. Efficacy was evaluated against an abrasivity-matched placebo formulation (0% CSPS) with additional abrasive silica replacing the CSPS, and two commercially available fluoride toothpastes as controls. After an initial lead-in period, subjects were randomized to one of the four study treatments and instructed to brush twice daily for the next 8 weeks. DH was assessed at baseline and following 4 and 8 weeks of treatment by response to tactile and evaporative (air) stimuli, and using a Dentine Hypersensitivity Experience Questionnaire (DHEQ; a validated quality-of-life measure for DH). RESULTS: A total of 134 subjects were randomized and completed the study. All treatments demonstrated statistically significant reductions in sensitivity from baseline at Week 4 and Week 8 for each clinical measure of sensitivity (all P ≤ 0.001). The 0% CSPS toothpaste demonstrated small but statistically significant reductions in Schiff sensitivity score compared with the other study toothpastes at Week 8 (all P< 0.05), whereas the experimental 5% CSPS toothpaste significantly improved the tactile threshold at Week 4 compared with the 0% CSPS toothpaste (P = 0.0467). The DHEQ responses did not reveal any consistent statistically significant within-treatment changes from baseline or between-treatment differences. Correlation analysis showed weak-to-moderate associations between the DHEQ outcomes and clinical endpoints. Study treatments were well tolerated. The treatment differences observed in this exploratory study were small and inconsistent between measures. The reasons for the inconsistencies are not clear but may be related to the properties of the abrasivity-matched 0% CSPS formulation, with the increased level of dental silica conferring an advantage in terms of reducing DH. The ability of dental silicas to occlude exposed dentin tubules and thereby reduce DH has been demonstrated in previous studies, and may warrant further clinical investigation.

Efficacy of an experimental toothpaste containing 5% calcium sodium phosphosilicate in the relief of dentin hypersensitivity: An 8-week randomized study (Study 2).

PURPOSE: To compare the efficacy of an experimental toothpaste containing 5% (w/w) calcium sodium phosphosilicate (CSPS) in relieving dentin hypersensitivity (DH) with that of control toothpastes containing no known anti-sensitivity ingredients. METHODS: This was the second of two exploratory, randomized, four-treatment, examiner-blind, parallel-design, single-site, 8-week studies in healthy subjects with self-reported and clinically diagnosed DH. After an initial lead-in period, subjects were randomized to one of four study treatments: the experimental toothpaste containing 5% CSPS with a modified surfactant system, developed to enhance its organoleptic properties; an abrasivity-matched placebo formulation (0% CSPS) with additional abrasive silica replacing the CSPS; or one of two commercially available fluoride toothpastes as controls. Subjects were instructed to brush twice daily for the next 8 weeks. DH was assessed at baseline and following 4 and 8 weeks of treatment by response to tactile and evaporative (air) stimuli, and using a Dentine Hypersensitivity Experience Questionnaire (DHEQ; a validated quality of life measure for DH). RESULTS: A total of 137 subjects were included in the efficacy analysis. The experimental 5% CSPS toothpaste demonstrated statistically significant reductions from baseline in sensitivity at Week 4 and Week 8 for each clinical measure (all P< 0.01). It also demonstrated significantly greater improvements in DH compared with the two control toothpastes for the majority of clinical measures at Week 4 (P ≤ 0.01) and for all clinical measures at Week 8 (all P < 0.01). The abrasivity-matched 0% CSPS toothpaste was associated with similar outcomes to the 5% CSPS toothpaste. The DHEQ responses did not reveal any consistent statistically significant within-treatment changes from baseline or between-treatment differences. Strong correlations with DHEQ outcomes were only observed for the subjects' sensitivity rating in response to evaporative (air) stimuli at Week 8. Study treatments were well tolerated.

A Randomized Clinical Trial Investigating the Effect of Particle Size of Calcium Sodium Phosphosilicate (CSPS) on the Efficacy of CSPS-containing Dentifrices for the Relief of Dentin Hypersensitivity.

OBJECTIVES: To investigate the effect of reducing the particle size of calcium sodium phosphosilicate (CSPS) bioactive glass from ~14 µm (NovaMin®) to ~4 µm (Vitryxx®), and of changing the fluoride source in a 5% CSPS dentifrice from sodium monofluorophosphate (SMFP) to sodium fluoride (NaF) on the efficacy of CSPS-containing dentifrices in dentin hypersensitivity (DH) relief. METHODS: A randomized, controlled, examiner-blind, five-treatment arm, parallel group, stratified, exploratory study of NaF dentifrices containing 2.5% or 5% small particle size CSPS (~4 µm), NaF or SMFP dentifrices containing 5% CSPS (~14 µm), and a regular fluoride dentifrice in healthy subjects with DH. Sensitivity to tactile stimulus (Yeaple probe) and evaporative (air) stimulus (Schiff Sensitivity Scale, visual analogue scale) was assessed at baseline and after one, two, four, and eight weeks' twice-daily treatment. The study was not statistically powered to detect significant between-treatment differences. RESULTS: One hundred thirty-three of 134 randomized subjects completed the study. All treatments showed similar, statistically significant (p < 0.007) improvements in DH compared to baseline at Weeks 2, 4, and 8. No trends favoring any specific treatment were observed. Treatments were generally well tolerated. CONCLUSIONS: The apparent absence of a positive treatment effect for the CSPS-containing dentifrices compared to the regular fluoride dentifrice is inconsistent with other previously reported efficacy studies for CSPS dentifrices.

A Randomized Clinical Study Investigating the Stain-Removal Potential of Two Experimental Dentifrices.

OBJECTIVE: To evaluate the ability of two experimental desensitizing dentifrices, both containing a chemical cleaning agent, one with ultra-low abrasivity and one with low abrasivity, a standard fluoride dentifrice, and a daily-use whitening dentifrice to remove extrinsic tooth stain. METHODS: This was a single-center, examiner-blind, randomized, controlled, four-treatment, parallel-group study in healthy adults. Extrinsic stain was evaluated using the Macpherson modification of the Lobene Stain Index (MLSI). At baseline, eligible subjects with a total MLSI (area x intensity [A x I]) score of 15 for the facial surfaces of the 12 anterior teeth were stratified (based on total MLSI [A x I] score [< 45 = low; ≥ 45 = high] and smoking status) and randomized to treatment with one of four dentifrices: an experimental ultra-low abrasivity desensitizing dentifrice (relative dentin abrasion [RDA] -12); an experimental low abrasivity desensitizing dentifrice (RDA -40); a standard fluoride dentifrice with moderate abrasivity (RDA -80); and a whitening dentifrice with higher abrasivity (RDA -142). Both desensitizing dentifrices contained 5% potassium nitrate and 5% sodium tripolyphosphate (a chemical cleaning agent). Treatment effects were evaluated after four and eight weeks of twice-daily brushing. RESULTS: In total, 142 subjects were randomized and 133 subjects completed the study. All study dentifrices demonstrated statistically significant reductions in extrinsic tooth stain from baseline after four and eight weeks of twice-daily use (p < 0.01). There were no statistically significant between-treatment differences for the primary variable (mean MLSI [A x I] score across all assessed sites) at four or eight weeks, and no notable trends were observed. CONCLUSION: All study dentifrices reduced extrinsic tooth stain. The experimental ultra-low and low abrasivity desensitizing dentifrices containing 5% sodium tripolyphosphate performed similarly to both a moderate abrasivity standard fluoride dentifrice and a higher abrasivity whitening dentifrice.

Preconception opioids interact with mouse strain to alter morphine withdrawal in the next generation.

RATIONALE: Transgenerational effects of preconception morphine exposure in female rats have been reported which suggest that epigenetic modifications triggered by female opioid exposure, even when that exposure ends several weeks prior to pregnancy, has significant ramifications for their future offspring. OBJECTIVE: The current study compares two mouse strains with well-established genetic variation in their response to mu opioid receptor agonists, C57BL/6J (BL6) and 129S1/svlmJ (129) to determine whether genetic background modifies the impact of preconception opioid exposure. METHODS: Adolescent females from both strains were injected daily with morphine for a total of 10 days using an increasing dosing regimen with controls receiving saline. Several weeks after their final injection, aged-matched BL6 and 129 morphine (Mor-F0) or saline (Sal-F0) females were mated with drug naïve males to generate Mor-F1 and Sal-F1 offspring, respectively. As adults, F1 mice were made morphine dependent using thrice daily morphine injections for 4 days. On day 5, mice were administered either saline or morphine followed 3 h later by naloxone. Behavioral and physiological signs of withdrawal were then measured. RESULTS: Regardless of strain or sex, morphine-dependent Mor-F1 mice had significantly lower levels of withdrawal-induced corticosterone but significantly higher glucose levels when compared to Sal-F1 controls. In contrast, both strain- and preconception opioid exposure effects on physical signs of morphine dependence were observed.

Increased rates of suicide ideation and attempts in rural dwellers following the SARS-CoV-2 pandemic.

PURPOSE: Those factors identified to increase the risk of suicide in rural dwellers were exacerbated by the SARS-CoV-2 pandemic, specifically economic factors, substance use, access to health care, and access to lethal weapons. Because the effects of SARS-CoV-2 on suicide ideation and attempts in rural populations have not been fully characterized in published literature, this study compares: (1) the rates of suicide ideation and attempts between the 6 months affected by SARS-CoV-2 to same months of the preceding year (3/18/2020-9/18/20; 3/18/2019-9/18/19), (2) demographics (ie, age, sex, residence, race, and ethnicity), and (3) the locations in which the encounters were billed (inpatient, outpatient, and emergency department). METHODS: Deidentified claims data associated with patient encounters billed for Suicide Ideation and Suicide Attempt were grouped based on time period and analyzed using descriptive statistics, incidence rate ratio (IRR), 2-sample t-test, chi-square test of association, or Fisher's exact test. FINDINGS: Suicidal ideation encounters increased in the 6 months post-SARS-CoV-2 when compared to the 6 months of the prior year (IRR = 1.19; P < .001). Males (IRR = 1.27, P < .001), those residing rural areas (IRR = 1.22, P = .01), and Black, non-Hispanic (IRR = 1.24, P = .024) were found to have increased rates of suicide ideation post-SARS-Cov-2. In adults, White, non-Hispanics (IRR = 1.16; P < .001) had increased rates of post-SARS-CoV-2. In the pediatric subset, those who were aged 14-17 (IRR = 1.50; P < .001), resided in rural areas (IRR = 1.61, P = .009), and idenitifed as Hispanic (IRR = 1.89; P = .037) or Black, non-Hispanic (IRR = 1.61, P = .009) had increased rates post-SARS-CoV-2. CONCLUSIONS: Our study identified rural dwellers to be at increased risk for suicide ideation.

Recommendation for changes to the guidelines of trauma patients with potential spinal injury within a regional UK ambulance trust.

Background: Spinal assessment and immobilisation has been a topic of debate for many years where, despite an emerging evidence base and the delivery of new guidance overseas, little has changed within UK pre-hospital practice. Since 2018, South East Coast Ambulance Service NHS Foundation Trust has spent time working with local trauma networks and expertise from within the region and international colleagues to develop a set of C-spine assessment and immobilisation guidelines that reflect the current best available international evidence and significant changes in international pre-hospital practice from settings such as Scandinavia and Australasia. Methods: A specialist group was commissioned to review the topic of pre-hospital spinal immobilisation and explore potential for evidence-based improvement. In conjunction with local trauma networks, subject matter experts and a thorough review of recent literature, a series of recommendations were made in order to improve spinal care within the authoring trust. Results: Seven recommendations were made, and an updated set of guidelines produced. These included the removal of semi-rigid collars from pre-hospital spinal immobilisation; the creation of two tiers of patients to ensure that the high-risk and low-risk populations are considered separately and an accompanying decision tool to safeguard both cohorts; an increased emphasis on the risk of spinal injury in the frail and older patient; an emphasis on spinal motion restriction rather than rigid immobilisation; an increased emphasis on self-extrication; and the use of a marker for emergency departments. Summary: An updated set of guidance has been produced using a combination of specialist and expert opinion alongside a literature review with close involvement of key stakeholders, both public and professional. The new guidance helps to ensure a patient-centred approach where each person is considered an individual with their risk of injury and management measures tailored to their specific needs.

Randomised methodology development study to investigate plaque removal efficacy of manual toothbrushes.

OBJECTIVES: This study aimed to evaluate plaque removal efficacy of toothbrushes to guide clinical model development. METHODS: This single-centre, randomised, controlled, examiner-blind, method development study included 80 healthy participants. Over 28 days, participants brushed twice-daily using a fluoride toothpaste and one of four marketed toothbrushes: Toothbrushes A (compact head) and B (regular head): medium-hard; flat trim; end-rounded bristles; Toothbrush C: medium-hard; end-rounded bristles; silky, tapered filaments; compact head; Toothbrush D: soft; tapered filaments; compact head. Supra-gingival plaque removal was evaluated immediately after single brushing events (Days 0, 7, 28, at study centre) and following 7- and 28-days' home use via Rustogi modified Navy Plaque Index (RPI) and Turesky modified Quigley Hein Plaque Index (TPI). RESULTS: All toothbrushes provided significant plaque removal after single-brushing events with change from Day 0 pre-brushing scores on RPI ranging from -0.10 to -0.16 (p<.0001) and on TPI ranging from -0.61 to -0.89 (p<.0001). Toothbrushes A and B showed significant (p<.05) pre-brushing RPI/TPI plaque reductions after 7- (-0.04/-0.06, respectively for RPI; -0.16/-0.20, respectively for TPI) and 28-days (-0.04/-0.03, respectively for RPI; -0.20/-0.11, respectively for TPI) use versus Day 0 pre-brushing (except Toothbrush B, Day 28, non-significant TPI). There were no significant differences with Toothbrush C. Toothbrush D TPI was significantly lower at both timepoints versus Day 0 pre-brushing (p<.05). Study toothbrushes were generally well-tolerated. CONCLUSION: The observations from this study showed how various aspects of a study design could impact toothbrushes performance. These data will inform the design of future clinical studies of plaque removal efficacy using manual toothbrushes. CLINICAL SIGNIFICANCE STATEMENT: Regular effective oral hygiene can help prevent and treat gingivitis, principally via twice-daily mechanical cleaning with a toothbrush. Data generated from this methodology development study will help to identify the key aspects which impact toothbrushes' performance and understand which one would be more suitable to answer questions of scientific interest. This study provides useful information for the design of future clinical trials to assess plaque removal efficacy of manual toothbrushes and generate results to inform clinical recommendations.

The UPTAKE study: a cross-sectional survey examining the insights and beliefs of the UK population on COVID-19 vaccine uptake and hesitancy.

OBJECTIVE: A key challenge towards a successful COVID-19 vaccine uptake is vaccine hesitancy. We examine and provide novel insights on the key drivers and barriers towards COVID-19 vaccine uptake. DESIGN: This study involved an anonymous cross-sectional online survey circulated across the UK in September 2020. The survey was designed to include several sections to collect demographic data and responses on (1) extent of agreement regarding various statements about COVID-19 and vaccinations, (2) previous vaccination habits (eg, if they had previously declined vaccination) and (3) interest in participation in vaccine trials. Multinominal logistic models examined demographic factors that may impact vaccine uptake. We used principle component analysis and text mining to explore perception related to vaccine uptake. SETTING: The survey was circulated through various media, including posts on social media networks (Facebook, Twitter, LinkedIn and Instagram), national radio, news articles, Clinical Research Network website and newsletter, and through 150 West Midlands general practices via a text messaging service. PARTICIPANTS: There were a total of 4884 respondents of which 9.44% were black, Asian and minority ethnic (BAME) group. The majority were women (n=3416, 69.9%) and of white ethnicity (n=4127, 84.5%). RESULTS: Regarding respondents, overall, 3873 (79.3%) were interested in taking approved COVID-19 vaccines, while 677 (13.9%) were unsure, and 334 (6.8%) would not take a vaccine. Participants aged over 70 years old (OR=4.63) and the BAME community (OR=5.48) were more likely to take an approved vaccine. Smokers (OR=0.45) and respondents with no known illness (OR=0.70) were less likely to accept approved vaccines. The study identified 16 key reasons for not accepting approved vaccines, the most common (60%) being the possibility of the COVID-19 vaccine having side effects. CONCLUSIONS: This study provides an insight into focusing on specific populations to reduce vaccine hesitancy. This proves crucial in managing the COVID-19 pandemic.

Hub-and-spoke model for thrombectomy service in UK NHS practice.

Mechanical thrombectomy is a highly effective but time dependent treatment for acute ischaemic stroke due to large vessel occlusion. In the UK, the national clinical guidelines for stroke and National Institute for Health and Care Excellence guidance endorses thrombectomy as an acute stroke treatment, and NHS England commissioned thrombectomy services. However, there are no UK 'real-world' data to verify the efficacy of the hub-and-spoke model in thrombectomy. There are currently 24 tertiary neuroscience centres in the UK that can provide thrombectomy treatment and many of these operate only within working hours. This study is the first to demonstrate that a hub-and-spoke thrombectomy service in routine UK 24/7 clinical practice is as effective and safe as in the setting of randomised controlled clinical trials. However, there are 9.3% of patients accepted for transfer to the thrombectomy centre who did not proceed to thrombectomy, mostly due to delays. Fifty-three per cent of thrombectomy cases were performed outside of standard working hours when transfer delays were increased. A 24/7 thrombectomy service is needed to maximise the benefit to all suitable patients. Measures, including improving workflow and optimising work forces, are needed to minimise the delays and continue to improve the service.

The UPTAKE study: implications for the future of COVID-19 vaccination trial recruitment in UK and beyond.

BACKGROUND: Developing a safe and effective vaccine will be the principal way of controlling the COVID-19 pandemic. However, current COVID-19 vaccination trials are not adequately representing a diverse participant population in terms of age, ethnicity and comorbidities. Achieving the representative recruitment targets that are adequately powered to the study remains one of the greatest challenges in clinical trial management. To ensure accuracy and generalisability of the safety and efficacy conclusions generated by clinical trials, it is crucial to recruit patient cohorts as representative as possible of the future target population. Missing these targets can lead to reduced validity of the study results and can often slow down drug development leading to costly delays. OBJECTIVE: This study explores the key factors related to perceptions and participation in vaccination trials. METHODS: This study involved an anonymous cross-sectional online survey circulated across the UK. Statistical analysis was done in six phases. Multi-nominal logistic models examined demographic and geographic factors that may impact vaccine uptake. RESULTS: The survey had 4884 participants of which 9.44% were Black Asian Minority Ethnic (BAME). Overall, 2020 (41.4%) respondents were interested in participating in vaccine trials; 27.6% of the respondents were not interested and 31.1% were unsure. The most interested groups were male (OR = 1.29), graduates (OR = 1.28), the 40-49 and 50-59 age groups (OR = 1.88 and OR = 1.46 respectively) and those with no health issues (OR = 1.06). The least interested groups were BAME (OR = 0.43), those from villages and small towns (OR = 0.66 and 0.54 respectively) and those aged 70 and above (OR = 1.11). CONCLUSIONS: In order to have a vaccination that is generalisable to the entire population, greater work needs to be done in engaging a diverse cohort of participants. Public health campaigns need to be targeted in improving trial recruitment rates for the elderly, BAME community and the less educated rural population.

Delineating Astrocytic Cytokine Responses in a Human Stem Cell Model of Neural Trauma.

Neuroinflammation has been shown to mediate the pathophysiological response following traumatic brain injury (TBI). Accumulating evidence implicates astrocytes as key immune cells within the central nervous system (CNS), displaying both pro- and anti-inflammatory properties. The aim of this study was to investigate how in vitro human astrocyte cultures respond to cytokines across a concentration range that approximates the aftermath of human TBI. To this end, enriched cultures of human induced pluripotent stem cell (iPSC)-derived astrocytes were exposed to interleukin-1ß (IL-1ß) (1-10,000 pg/mL), IL-4 (1-10,000 pg/mL), IL-6 (100-1,000,000 pg/mL), IL-10 (1-10,000 pg/mL) and tumor necrosis factor (TNF)-α (1-10,000 pg/mL). After 1, 24, 48 and 72 h, cultures were fixed and immunolabeled, and the secretome/supernatant was analyzed at 24, 48, and 72 h using a human cytokine/chemokine 39-plex Luminex assay. Data were compared to previous in vitro studies of neuronal cultures and clinical TBI studies. The secretome revealed concentration-, time- and/or both concentration- and time-dependent production of downstream cytokines (29, 21, and 17 cytokines, respectively, p<0.05). IL-1ß exposure generated the most profound downstream response (27 cytokines), IL-6 and TNF had intermediate responses (13 and 11 cytokines, respectively), whereas IL-4 and IL-10 only led to weak responses over time or in escalating concentration (8 and 8 cytokines, respectively). Notably, expression of IL-1ß, IL-6, and TNF cytokine receptor mRNA was higher in astrocyte cultures than in neuronal cultures. Several secreted cytokines had temporal trajectories, which corresponded to those seen in the aftermath of human TBI. In summary, iPSC-derived astrocyte cultures exposed to cytokine concentrations reflecting those in TBI generated an increased downstream cytokine production, particularly IL-1ß. Although more work is needed to better understand how different cells in the CNS respond to the neuroinflammatory milieu after TBI, our data shows that iPSC-derived astrocytes represent a tractable model to study cytokine stimulation in a cell type-specific manner.

Low Incidence of Pelvic Sepsis after Hartmann's Procedure: Radiation Therapy May Be a Risk Factor.

PURPOSE: Hartmann's procedure is a well-established alternative in colorectal surgery when a primary anastomosis is contraindicated. However, the rectal remnant may cause complications. This study was designed to investigate the occurrence of pelvic sepsis after Hartmann's procedure and identify possible risk factors. METHODS: All patients who underwent Hartmann's procedure between 2005 and 2012 were identified by the in-hospital registry. Information about pelvic sepsis and potential preoperative, perioperative, and postoperative risk factors was obtained by review of the medical records. RESULTS: 172 patients were identified (97 females); they were aged 74 ± 11 years. Surgery was performed due to cancer (49%) or diverticulitis (35%) and other benign disease (16%). Rectal transection was carried out anywhere between the pelvic floor and the promontory. Pelvic sepsis developed in 6.4% (11/172) of patients. Pelvic sepsis was associated with preoperative radiotherapy (p = 0.03) and Hinchey grade III and IV (p = 0.02) in those patients who underwent Hartmann's procedure for diverticular disease. CONCLUSION: Hartmann's procedure is a safe operation when an anastomosis is contraindicated since the incidence of pelvic sepsis is low. Preoperative radiotherapy and Hinchey grade III and IV may be risk factors for the development of pelvic sepsis.

Efficacy of a 3% potassium nitrate mouthrinse for the relief of dentinal hypersensitivity: An 8-week randomized controlled study.

BACKGROUND: Mouthrinses containing potassium salts have been shown to be effective for the relief of dentinal hypersensitivity (DH) when used adjunctively to toothbrushing with a nonsensitivity toothpaste. METHODS: The authors conducted a randomized, 8-week, single-center, examiner-blinded, parallel-group clinical trial with 191 participants with DH. Participants were randomized to twice-daily use of either 3% potassium nitrate (KNO3) mouthrinse plus fluoride toothpaste or the same fluoride toothpaste alone. The primary outcome was change from baseline in response to an evaporative (air) stimulus at 8 weeks, measured using the Schiff sensitivity scale. Secondary outcomes were response to an evaporative (air) stimulus with the Schiff sensitivity scale (4 weeks) and a visual rating scale (4 and 8 weeks) and response to a tactile stimulus (4 and 8 weeks). RESULTS: Both groups showed statistically significant improvements in evaporative (air) sensitivity from baseline after 4 and 8 weeks (P < .0001). At weeks 4 and 8, the authors observed significant improvements from baseline in tactile sensitivity only in the KNO3 mouthrinse group (P < .0001). Between-treatment comparisons for all sensitivity measures at both time points showed statistically significantly greater DH reductions in the KNO3 mouthrinse group compared with the toothpaste-alone group (P = .0004 for the visual rating scale at week 4; P < .0001 for all other measures and time points). Treatments were generally well tolerated. CONCLUSIONS: Twice-daily use of a 3% KNO3 mouthrinse, adjunctive to toothbrushing with fluoride toothpaste, provided significant improvements in DH compared with fluoride toothpaste alone. PRACTICAL IMPLICATIONS: Addition of 3% KNO3 mouthrinse to a typical oral hygiene regimen of toothbrushing with fluoride toothpaste provides an alternative strategy for the management of DH. ClinicalTrials.gov: NCT02226562.

What is the Impact of Volunteers Providing Care and Support for People with Dementia in Acute Hospitals? A Systematic Review.

A quarter of acute hospital beds are occupied by people with dementia, and a hospital stay may impact negatively on their health and wellbeing. The development and implementation of volunteers to provide social, activity-based, one-to-one support for people with dementia in acute hospitals has become routine practice. However, the evidence to support this practice has not been identified or evaluated. This systematic review considers the effect of volunteers on the care and experience of people with co-morbid cognitive impairment/dementia in acute hospitals. The systematic search identified 444 papers, although only three papers included specific analysis relating to the impact of volunteers. The evidence suggests volunteers may have potential to enhance the experiences of people with dementia in acute hospitals; however, there is currently a marked lack of evidence to support the widespread implementation of volunteers. There is therefore an urgent need for multi-site robust research to provide evidence of the impact of volunteers supporting people with cognitive impairment/dementia during an acute hospital stay.

A Review of the Role of Carcinoembryonic Antigen in Clinical Practice.

Carcinoembryonic antigen (CEA) is not normally produced in significant quantities after birth but is elevated in colorectal cancer. The aim of this review was to define the current role of CEA and how best to investigate patients with elevated CEA levels. A systematic review of CEA was performed, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies were identified from PubMed, Cochrane library, and controlled trials registers. We identified 2,712 papers of which 34 were relevant. Analysis of these papers found higher preoperative CEA levels were associated with advanced or metastatic disease and thus poorer prognosis. Postoperatively, failure of CEA to return to normal was found to be indicative of residual or recurrent disease. However, measurement of CEA levels alone was not sufficient to improve survival rates. Two algorithms are proposed to guide investigation of patients with elevated CEA: one for patients with elevated CEA after CRC resection, and another for patients with de novo elevated CEA. CEA measurement has an important role in the investigation, management and follow-up of patients with colorectal cancer.