A two-centre experience of tonsil biopsies in the investigation of patients with tonsillar asymmetry.

INTRODUCTION: We aim to evaluate our experience of tonsil biopsies in the investigation of patients presenting with asymmetrical tonsils. METHODS: A two-centre retrospective analysis of all patients who underwent histology sampling of the palatine tonsils between 1 January 2013 and 31 December 2018 was completed. Data collected included patient demographics, method of obtaining tonsil tissue, histological diagnosis and need for repeat tissue sampling. A follow-up period of 36 months was allowed to establish whether any patients re-presented with missed diagnoses. RESULTS: In total, 937 patients were included for analysis: 375 (40.0%) had a biopsy, of which 191 (50.9%) were performed in clinic. The mean duration from initial appointment with the ear, nose and throat clinic to tissue sample collection was 17.6 days (range 0-327 days) for all biopsies, reducing to 0.2 days (range 0-17 days) for biopsies performed in clinic. This was significantly shorter than for tonsillectomies (mean 38.9 days, range 0-444 days; p<0.05). Of the patients who underwent tonsil biopsy, six (1.6%) had malignancy that was not unequivocally diagnosed on initial biopsy. In all six patients, prior clinical suspicion was high, and repeat tissue sampling was undertaken on receipt of negative histology results. CONCLUSIONS: Tonsil biopsy is a viable alternative to tonsillectomy for histology in the assessment of tonsil asymmetry. Tonsil biopsy in the outpatient setting has reduced surgical morbidity, significantly less delay in diagnosis, less inconvenience for patients and lower healthcare costs compared with formal tonsillectomy. Although tonsil biopsies should not be used in isolation, they can be useful in the investigation of patients presenting with tonsillar asymmetry.

Association between Hashimoto's thyroiditis and melanoma: a retrospective matched cohort study.

An inflammatory microenvironment has been shown to increase risk for malignant melanoma, suggesting that melanoma may be related to a pro-inflammatory state. Though Hashimoto's thyroiditis is one of the most common autoimmune diseases, there are no investigations of its relationship with melanoma. We aim to determine if Hashimoto's increases risk of developing melanoma. A retrospective, validated cohort of patients with a diagnosis of Hashimoto's between 2005 and 2020 were identified using the Olmsted County database. Patients were age and sex matched to controls without a Hashimoto's diagnosis. The primary outcomes were development of melanoma and time to first melanoma diagnosis. 4805 patients were included in the study, with 1726 (36%) having a diagnosis of Hashimoto's. Hashimoto's patients had no significant difference in risk of melanoma (relative risk 0.96, 95% CI 0.78-1.17) or nonmelanoma skin cancer (relative risk 0.95, 95% CI 0.86-1.06) compared with matched controls. This suggests that the local proinflammatory environment present in Hashimoto's does not contribute significantly to melanoma risk. Larger studies may be needed to further characterize the relationship between these diseases.

Spontaneous shunt independence in paediatric tumour-related hydrocephalus: case series and review of the literature.

PURPOSE: Hydrocephalus is commonly associated with paediatric posterior fossa tumours and their resection. This is commonly managed by ventriculoperitoneal shunt insertion, which is associated with a lifelong risk of malfunction, necessitating revisional surgery. Few opportunities ever arise for the patient to be free of the shunt and this risk. We describe three patients shunted for tumour-related hydrocephalus who subsequently developed spontaneous shunt independence. We discuss this in the context of the literature. METHODS: A single-centre retrospective case series analysis was performed using a departmental database. Case notes were retrieved from a local electronic records database, and images were reviewed using national Picture Archiving and Communication Systems. RESULTS: Over a 10-year period, 28 patients underwent ventriculoperitoneal shunt insertion for tumour-related hydrocephalus. Of these, 3 patients (10.7%) went on to have their shunts successfully removed. Age at presentation varied from 1 to 16 years. In all cases, the patient required shunt externalization due to shunt or intra-abdominal infection. This was used as an opportunity to challenge the need for ongoing cerebrospinal fluid (CSF) diversion. In one case, this occurred only several months after a shunt blockage with intracranial pressure monitoring that proved her shunt dependence. All three patients tolerated this challenge, their shunt systems were removed without complication, and they remain free of hydrocephalus at last follow-up. CONCLUSION: These cases reflect our poor understanding of the heterogenous physiology of patients with shunted hydrocephalus and underline the importance of challenging the need for CSF diversion at any appropriate opportunity.

CELPI: trial protocol for a randomised controlled trial of a Carer End of Life Planning Intervention in people dying with dementia.

BACKGROUND: Dementia is a leading cause of death in developed nations. Despite an often distressing and symptom laden end of life, there are systematic barriers to accessing palliative care in older people dying of dementia. Evidence exists that 70% of people living with severe dementia attend an emergency department (ED) in their last year of life. The aim of this trial is to test whether a Carer End of Life Planning Intervention (CELPI), co-designed by consumers, clinicians and content specialists, improves access to end of life care for older people with severe dementia, using an ED visit as a catalyst for recognising unmet needs and specialist palliative care referral where indicated. METHODS: A randomised controlled trial (RCT) enrolling at six EDs across three states in Australia will be conducted, enrolling four hundred and forty dyads comprising a person with severe dementia aged ≥ 65 years, and their primary carer. Participants will be randomly allocated to CELPI or the control group. CELPI incorporates a structured carer needs assessment and referral to specialist palliative care services where indicated by patient symptom burden and needs assessment. The primary outcome measure is death of the person with dementia in the carer-nominated preferred location. Secondary outcomes include carer reported quality of life of the person dying of dementia, hospital bed day occupancy in the last 12 months of life, and carer stress. An economic evaluation from the perspective of a health funder will be conducted. DISCUSSION: CELPI seeks to support carers and provide optimal end of life care for the person dying of dementia. This trial will provide high level evidence as to the clinical and cost effectiveness of this intervention. TRIAL REGISTRATION: ACTRN12622000611729 registered 22/04/2022.

Effect of Varenicline on Tardive Dyskinesia: A Pilot Study.

OBJECTIVE: Although evidence implicates striatal cholinergic impairment as a mechanism underlying tardive dyskinesia, trials of nonspecific cholinergic agents have been inconclusive. As a partial agonist at specific nicotinic receptor subtypes, varenicline reduces drug-induced dyskinesias in animal models suggesting promise as a treatment for tardive dyskinesia. METHODS: Three schizophrenia patients with tardive dyskinesia who were smokers underwent an open trial of varenicline. After a 2-week baseline, subjects received varenicline 1 mg twice daily. Changes from baseline on the Abnormal Involuntary Movement Scale were measured after a 4-week varenicline stabilization period, and 6 weeks after the smoking quit date in one patient. RESULTS: Varenicline had no effect on mean Abnormal Involuntary Movement Scale scores after 4 weeks. Although smoking decreased after 4 weeks on varenicline and diminished further in one patient after 10 weeks, this also appeared to have no effect on ratings of tardive dyskinesia. CONCLUSION: In contrast to animal models, no significant change in tardive dyskinesia occurred in response to varenicline replacement in three schizophrenia patients. Further investigations of cholinergic mechanisms in tardive dyskinesia are worthwhile as agents for specific cholinergic targets become available for treatment. In addition, treatment trials of tardive dyskinesia should control for smoking status, while patients on antipsychotics receiving nicotine replacement therapies for smoking should be studied further for changes in movement.

The COVID-19 Pandemic: The effect on open lower limb fractures in a London major trauma centre - a plastic surgery perspective.

BACKGROUND: COVID-19 has created huge pressures on healthcare systems. The ongoing provision of major trauma services during this time has proved challenging. We report our experience of managing open lower limb fractures (oLLFs) during the pandemic in a London major trauma centre (MTC). METHODS: This was a prospective study of all open lower limb fractures presenting to our unit over the initial 48 days of UK government lockdown - 24th March till 10th May 2020. Results were compared to the same time period in 2019 retrospectively. Epidemiological data, mechanism, Gustilo-Anderson (G-A) severity grading, time to initial debridement and definitive coverage were analysed. RESULTS: There was a 64% reduction in emergency department (ED) attendances (25,264 vs 9042). There was an 18% reduction in oLLFs (22 vs 18). Approximately three-quarters of injuries were in males across both cohorts (77% vs 78%) and tended to occur in younger patients (median age, 37 vs 35). Road-traffic-accidents (RTAs) were the most common injury mechanism in both 2019 and lockdown, but a rise in jumpers from height was seen in the latter. A similar pattern of G-A severities were seen, however only 3 injuries during lockdown required major soft tissue reconstruction. There was no significant difference in times taken for initial debridement (p = 0.72786) or definitive wound coverage (p = 0.16152). A greater proportion of independent operating was seen during lockdown between orthopaedics and plastic surgery. CONCLUSIONS: Despite government lockdown measures, oLLFs still placed significant burden on our MTC. Notwithstanding significant staffing alterations and theatre pressures, we have been able to ensure these lower limb emergencies remain a surgical priority and have managed to utilise resources appropriately.

Graphene Oxide as a Multifunctional Platform for Intracellular Delivery, Imaging, and Cancer Sensing.

Graphene oxide (GO), the most common derivative of graphene, is an exceptional nanomaterial that possesses multiple physical properties critical for biomedical applications. GO exhibits pH-dependent fluorescence emission in the visible/near-infrared, providing a possibility of molecular imaging and pH-sensing. It is also water soluble and has a substantial platform for functionalization, allowing for the delivery of multiple therapeutics. GO physical properties are modified to enhance cellular internalization, producing fluorescent nanoflakes with low (<15%) cytotoxicity at the imaging concentrations of 15 µg/mL. As a result, at lower flake sizes GO rapidly internalizes into HeLa cells with the following 70% fluorescence based clearance at 24 h, assessed by its characteristic emission in red/near-IR. pH-dependence of GO emission is utilized to provide the sensing of acidic extracellular environments of cancer cells. The results demonstrate diminishing green/red (550/630 nm) fluorescence intensity ratios for HeLa and MCF-7 cancer cells in comparison to HEK-293 healthy cells suggesting a potential use of GO as a non-invasive optical sensor for cancer microenvironments. The results of this work demonstrate the potential of GO as a novel multifunctional platform for therapeutic delivery, biological imaging and cancer sensing.

Bacteroidales recruit IL-6-producing intraepithelial lymphocytes in the colon to promote barrier integrity.

Interactions between the microbiota and distal gut are important for the maintenance of a healthy intestinal barrier; dysbiosis of intestinal microbial communities has emerged as a likely contributor to diseases that arise at the level of the mucosa. Intraepithelial lymphocytes (IELs) are positioned within the epithelial barrier, and in the small intestine they function to maintain epithelial homeostasis. We hypothesized that colon IELs promote epithelial barrier function through the expression of cytokines in response to interactions with commensal bacteria. Profiling of bacterial 16S ribosomal RNA revealed that candidate bacteria in the order Bacteroidales are sufficient to promote IEL presence in the colon that in turn produce interleukin-6 (IL-6) in a MyD88 (myeloid differentiation primary response 88)-dependent manner. IEL-derived IL-6 is functionally important in the maintenance of the epithelial barrier as IL-6-/- mice were noted to have increased paracellular permeability, decreased claudin-1 expression, and a thinner mucus gel layer, all of which were reversed by transfer of IL-6+/+ IELs, leading to protection of mice in response to Citrobacter rodentium infection. Therefore, we conclude that microbiota provide a homeostatic role for epithelial barrier function through regulation of IEL-derived IL-6.

Experimental demonstration of low laser-plasma instabilities in gas-filled spherical hohlraums at laser injection angle designed for ignition target.

Octahedral spherical hohlraums with a single laser ring at an injection angle of 55^{∘} are attractive concepts for laser indirect drive due to the potential for achieving the x-ray drive symmetry required for high convergence implosions. Laser-plasma instabilities, however, are a concern given the long laser propagation path in such hohlraums. Significant stimulated Raman scattering has been observed in cylindrical hohlraums with similar laser propagation paths during the ignition campaign on the National Ignition Facility (NIF). In this Rapid Communication, experiments demonstrating low levels of laser-driven plasma instability (LPI) in spherical hohlraums with a laser injection angle of 55^{∘} are reported and compared to that observed with cylindrical hohlraums with injection angles of 28.5^{∘} and 55^{∘}, similar to that of the NIF. Significant LPI is observed with the laser injection of 28.5^{∘} in the cylindrical hohlraum where the propagation path is similar to the 55^{∘} injection angle for the spherical hohlraum. The experiments are performed on the SGIII laser facility with a total 0.35-µm incident energy of 93 kJ in a 3 nsec pulse. These experiments demonstrate the role of hohlraum geometry in LPI and demonstrate the need for systematic experiments for choosing the optimal configuration for ignition studies with indirect drive inertial confinement fusion.

Drug-Induced Extrapyramidal Syndromes: Implications for Contemporary Practice.

The development of drugs to treat psychosis is a fascinating nexus for understanding mechanisms underlying disorders of mind and movement. Although the risk of drug-induced extrapyramidal syndromes has been mitigated by the acceptance of less potent dopamine antagonists, expansive marketing and off-label use has increased the number of susceptible people who may be at risk for these neurologic effects. Clinicians need to be familiar with advances in diagnosis and management, which are reviewed herein. A better understanding of drug-induced effects on the motor circuit may improve patient safety, enhance antipsychotic effectiveness, and provide insights into mechanisms underlying antipsychotic activity in parallel brain circuits.

The risk of oesophageal adenocarcinoma in a prospectively recruited Barrett's oesophagus cohort.

BACKGROUND: Varying rates of oesophageal adenocarcinoma (OAC) complicating Barrett's oesophagus (BO) have been reported. Recent studies and meta-analyses suggest a lower incidence, questioning the value of endoscopic surveillance. AIM: We aimed to retrospectively examine the rate of OAC, risk factors and causes of death in a prospectively recruited BO cohort. METHODS: Data from patients with BO from a cohort from 1982-2007 were studied. Patients were subdivided into surveyed, failed to attend surveillance and unfit for surveillance. Standardised mortality ratios (SMR) were calculated for common causes of death. Cox proportional hazards models were used to determine which factors were associated with progression to OAC. RESULTS: In total, 671 BO patients (61% male) were studied; 37 (76% male) were diagnosed with OAC. OAC incidence was 0.47% per annum and stable across three decades (1982-1991 0.56%, 1992-2001 0.46%, 2002-2012 0.41% (p = 0.8)). All-cause mortality was increased for the whole cohort (SMR 163(95% CI 145-183)). Mortality from OAC appeared higher in patients who failed to attend surveillance (SMR 3216(95% CI 1543-5916)) compared with surveyed (SMR 1753(95% CI 933-2998)) and those unfit for surveillance due to co-morbidity (SMR 440(95% CI 143-1025)). Multivariable analysis identified low-grade dysplasia (HR 4.4(95% CI 1.56-12.43), p = 0.005) and length of BO (HR 1.2(95% (1.1-1.3)), p < 0.001)) as associated with OAC. CONCLUSIONS: Progression to OAC appeared stable over three decades at 0.47% per annum. Patients with BO had a modest increase in all-cause mortality and a large increase in OAC mortality, particularly if fit for surveillance. Low-grade dysplasia and the length of the BO segment were associated with developing OAC.

Recurrent Idiopathic Catatonia: Implications beyond the Diagnostic and Statistical Manual of Mental Disorders 5th Edition.

We describe a case of recurrent, life-threatening, catatonic stupor, without evidence of any associated medical, toxic or mental disorder. This case provides support for the inclusion of a separate category of "unspecified catatonia" in the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) to be used to classify idiopathic cases, which appears to be consistent with Kahlbaum's concept of catatonia as a distinct disease state. But beyond the limited, cross-sectional, syndromal approach adopted in DSM-5, this case more importantly illustrates the prognostic and therapeutic significance of the longitudinal course of illness in differentiating cases of catatonia, which is better defined in the Wernicke-Kleist-Leonhard classification system. The importance of differentiating cases of catatonia is further supported by the efficacy of antipsychotics in treatment of this case, contrary to conventional guidelines.

Contribution of epithelial innate immunity to systemic protection afforded by prolyl hydroxylase inhibition in murine colitis.

Pharmacological stabilization of hypoxia-inducible factor (HIF) through prolyl hydroxylase (PHD) inhibition limits mucosal damage associated with models of murine colitis. However, little is known about how PHD inhibitors (PHDi) influence systemic immune function during mucosal inflammation or the relative importance of immunological changes to mucosal protection. We hypothesized that PHDi enhances systemic innate immune responses to colitis-associated bacteremia. Mice with colitis induced by trinitrobenzene sulfonic acid were treated with AKB-4924, a new HIF-1 isoform-predominant PHDi, and clinical, immunological, and biochemical endpoints were assessed. Administration of AKB-4924 led to significantly reduced weight loss and disease activity compared with vehicle controls. Treated groups were pyrexic but did not become subsequently hypothermic. PHDi treatment augmented epithelial barrier function and led to an approximately 50-fold reduction in serum endotoxin during colitis. AKB-4924 also decreased cytokines involved in pyrogenesis and hypothermia, significantly reducing serum levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α while increasing IL-10. Treatment offered no protection against colitis in epithelial-specific HIF-1α-deficient mice, strongly implicating epithelial HIF-1α as the tissue target for AKB-4924-mediated protection. Taken together, these results indicate that inhibition of prolyl hydroxylase with AKB-4924 enhances innate immunity and identifies that the epithelium is a central site of inflammatory protection afforded by PHDi in murine colitis.

Skeletal muscle adaptations to physical inactivity and subsequent retraining in young men.

Skeletal muscle structure and function are markedly affected by chronic disuse. With unloading, muscle mass is lost at rate of about 0.4 %/day but little is known about the recovery of muscle mass and strength following disuse. Here we report an extensive data set describing in detail skeletal muscle adaptations in structure and function in response to both disuse and retraining. Eight young men (23 ± 2.2 years) underwent 3 weeks of unilateral lower limb suspension (ULLS) followed by a 3-week resistance training recovery program. Knee extensor isometric torque, voluntary activation, quadriceps femoris (QF) muscle volume (QFvol), fascicle length (Lf) and pennation angle (θ), physiological cross-sectional area (PCSA) of all four heads of the QF muscle, were measured before, after ULLS, and post-ULLS-resistance training. Needle biopsies were taken from the vastus lateralis muscle of a subgroup (n = 6) of the same subjects and cross sectional area of individual muscle s and myosin content of muscle samples were determined. Following 3 weeks of ULLS, isometric torque decreased by 26 %, PCSA by 3 %, QFvol by 10 %. Lf and θ of all four heads of QF significantly decreased (p ≤ 0.05). Following the 3-week retraining period, isometric torque, PCSA, QFvol, Lf and θ of all four heads of QF were all fully restored to pre ULLS values. CSA of individual muscle fibres and myosin content of muscle samples decreased by 26 and 35 % respectively (post-ULLS) and recovered to almost pre-ULLS values following retraining. There were no significant changes in voluntary activation of the quadriceps muscles in response to either ULLS or subsequent retraining. These results indicate that: (1) the loss of muscle force with 3-week unloading in humans is mostly explained by muscle atrophy and by a decrease in myosin content and, (2) all the neuromuscular changes induced by this model of disuse can be fully restored after a resistance training intervention of equal duration.

Movement disorders induced by antipsychotic drugs: implications of the CATIE schizophrenia trial.

Drug-induced movement disorders have dramatically declined with the widespread use of second-generation antipsychotics, but remain important in clinical practice and for understanding antipsychotic pharmacology. The diagnosis and management of dystonia, parkinsonism, akathisia, catatonia, neuroleptic malignant syndrome, and tardive dyskinesia are reviewed in relation to the decreased liability of the second-generation antipsychotics contrasted with evidence from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial. Data from the CATIE trial imply that advantages of second-generation antipsychotics in significantly reducing extrapyramidal side effects compared with haloperidol may be diminished when compared with modest doses of lower-potency first-generation drugs.

The validity and reliability of an interactive computer tobacco and alcohol use survey in general practice.

BACKGROUND: Uncertainty regarding the accuracy of the computer as a data collection or patient screening tool persists. Previous research evaluating the validity of computer health surveys have tended to compare those responses to that of paper survey or clinical interview (as the gold standard). This approach is limited as it assumes that the paper version of the self-report survey is valid and an appropriate gold standard. OBJECTIVES: First, to compare the accuracy of computer and paper methods of assessing self-reported smoking and alcohol use in general practice with biochemical measures as gold standard. Second, to compare the test re-test reliability of computer administration, paper administration and mixed methods of assessing self-reported smoking status and alcohol use in general practice. METHODS: A randomised cross-over design was used. Consenting patients were randomly assigned to one of four groups; Group 1. C-C : completing a computer survey at the time of that consultation (Time 1) and a computer survey 4-7 days later (Time 2); Group 2. C-P: completing a computer survey at Time 1 and a paper survey at Time 2; Group 3. P-C: completing a paper survey at Time 1 and a computer survey at Time 2; and Group 4. P-P: completing a paper survey at Time 1 and 2. At Time 1 all participants also completed biochemical measures to validate self-reported smoking status (expired air carbon monoxide breath test) and alcohol consumption (ethyl alcohol urine assay). RESULTS: Of the 618 who were eligible, 575 (93%) consented to completing the Time 1 surveys. Of these, 71% (N=411) completed Time 2 surveys. Compared to CO, the computer smoking self-report survey demonstrated 91% sensitivity, 94% specificity, 75% positive predictive value (PPV) and 98% negative predictive value (NPV). The equivalent paper survey demonstrated 86% sensitivity, 95% specificity, 80% PPV, and 96% NPV. Compared to urine assay, the computer alcohol use self-report survey demonstrated 92% sensitivity, 50% specificity, 10% PPV and 99% NPV. The equivalent paper survey demonstrated 75% sensitivity, 57% specificity, 6% PPV, and 98% NPV. Level of agreement of smoking self-reports at Time 1 and Time 2 revealed kappa coefficients ranging from 0.95 to 0.98 in each group and hazardous alcohol use self-reports at Time 1 and Time 2 revealed kappa coefficients ranging from 0.90 to 0.96 in each group. CONCLUSION: The collection of self-reported health risk information is equally accurate and reliable using computer interface in the general practice setting as traditional paper survey. Computer survey appears highly reliable and accurate for the measurement of smoking status. Further research is needed to confirm the adequacy of the quantity/frequency measure in detecting those who drink alcohol. Interactive computer administered health surveys offer a number of advantages to researchers and clinicians and further research is warranted.