Training during the COVID-19 pandemic: the experience of public health registrars in the London and Kent, Surrey, Sussex training programme.

BACKGROUND: Public Health registrars (SpRs) were an important component of the workforce that contributed to the COVID-19 response. This study explores their contribution and the impact the early stages of the pandemic had on their learning and training. METHODS: Data were collected from SpRs in the London and Kent, Surrey, Sussex training programme between July and September 2020 through a mixture of questionnaires and semi-structured interviews. A thematic analysis of interview transcripts was undertaken to identify themes. RESULTS: 35/128 SpRs responded to the survey and 11 were interviewed. SpRs were placed across a range of organizations and made a significant contribution to the COVID-19 response. Overall, SpRs learned important skills but working on the response may for some have impacted negatively on training. A number of facilitators and barriers to learning were identified. CONCLUSION: The study findings highlight the opportunities for learning created by the pandemic. However, changing projects and the desire of SpRs to contribute to the response meant the impacts on training were mixed. Future deployment of SpRs should consider the balance of responsibility and pace when delegating work, as well as the need to supervise effectively and support remote working to maintain good mental wellbeing.

Responding to eruptive transitions during the 2020-2021 eruption of La Soufrière volcano, St. Vincent.

A critical challenge during volcanic emergencies is responding to rapid changes in eruptive behaviour. Actionable advice, essential in times of rising uncertainty, demands the rapid synthesis and communication of multiple datasets with prognoses. The 2020-2021 eruption of La Soufrière volcano exemplifies these challenges: a series of explosions from 9-22 April 2021 was preceded by three months of effusive activity, which commenced with a remarkably low level of detected unrest. Here we show how the development of an evolving conceptual model, and the expression of uncertainties via both elicitation and scenarios associated with this model, were key to anticipating this transition. This not only required input from multiple monitoring datasets but contextualisation via state-of-the-art hazard assessments, and evidence-based knowledge of critical decision-making timescales and community needs. In addition, we share strategies employed as a consequence of constraints on recognising and responding to eruptive transitions in a resource-constrained setting, which may guide similarly challenged volcano observatories worldwide.

Is decolonization to prevent Panton-Valentine leukocidin-positive Staphylococcus aureus infection in the population effective? A systematic review.

Panton-Valentine leukocidin (PVL) -producing Staphylococcus aureus is associated with recurrent skin and soft tissue infections and occasionally invasive infections. There is limited evidence to support current public health guidance on decolonization of cases and household contacts. This systematic review (CRD42020189906) investigated the efficacy of decolonization against PVL-positive S. aureus to inform future public health practice. It included studies of cases with PVL-positive infections providing information on the efficacy of decolonization of cases, carriers, or contacts of cases. Studies were assessed for the risk of bias using the GRADE approach and summarized to inform a narrative synthesis. The search identified 20, mostly observational, studies with small samples and lacking control groups. Studies with longer follow-ups found that, while early post-decolonization screening was negative for most individuals, testing over subsequent months identified re-colonization in some. There is no high-quality evidence to show whether decolonization is effective in reducing (re)infection or long-term carriage of PVL-positive S. aureus and the low-quality evidence available indicates it may not be effective in eradicating carriage or reducing future disease. Furthermore, there may be risks associated with decolonization, e.g., potentially increased risk of infection from other microbes, opportunity costs and negative impacts of repeated testing for asymptomatic carriage. Further research is required to better understand what affects the ability of decolonization efforts to reduce risk to cases and their contacts, including strain, host and environmental factors.

Immune and non-immune functions of adipose tissue leukocytes.

Adipose tissue is a complex dynamic organ with whole-body immunometabolic influence. Much of the work into understanding the role of immune cells in adipose tissue has been in the context of obesity. These investigations have also uncovered a range of typical (immune) and non-typical functions exerted by adipose tissue leukocytes. Here we provide an overview of the adipose tissue immune system, including its role as an immune reservoir in the whole-body response to infection and as a site of parasitic and viral infections. We also describe the functional roles of specialized immunological structures found within adipose tissue. However, our main focus is on the recently discovered 'non-immune' functions of adipose tissue immune cells, which include the regulation of adipocyte homeostasis, as well as responses to changing nutrient status and body temperature. In doing so, we outline the therapeutic potential of the adipose tissue immune system in health and disease.

Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis.

AIMS/HYPOTHESIS: The innate immune cells, invariant natural killer T cells (iNKT cells), are implicated in the pathogenesis of psoriasis, an inflammatory condition associated with obesity and other metabolic diseases, such as diabetes and dyslipidaemia. We observed an improvement in psoriasis severity in a patient within days of starting treatment with an incretin-mimetic, glucagon-like peptide-1 (GLP-1) receptor agonist. This was independent of change in glycaemic control. We proposed that this unexpected clinical outcome resulted from a direct effect of GLP-1 on iNKT cells. METHODS: We measured circulating and psoriatic plaque iNKT cell numbers in two patients with type 2 diabetes and psoriasis before and after commencing GLP-1 analogue therapy. In addition, we investigated the in vitro effects of GLP-1 on iNKT cells and looked for a functional GLP-1 receptor on these cells. RESULTS: The Psoriasis Area and Severity Index improved in both patients following 6 weeks of GLP-1 analogue therapy. This was associated with an alteration in iNKT cell number, with an increased number in the circulation and a decreased number in psoriatic plaques. The GLP-1 receptor was expressed on iNKT cells, and GLP-1 induced a dose-dependent inhibition of iNKT cell cytokine secretion, but not cytolytic degranulation in vitro. CONCLUSIONS/INTERPRETATION: The clinical effect observed and the direct interaction between GLP-1 and the immune system raise the possibility of therapeutic applications for GLP-1 in inflammatory conditions such as psoriasis.

Natural killer cells in psoriasis.

Psoriasis is one of the most common immune-mediated disorders. There is evidence that it is mediated by Th1 and, more recently, Th17 cells. The cytokine pattern, particularly the dominance of TNF-α, implicates the innate immune system in psoriasis pathogenesis. Of the many components of the innate immune system known to be involved in psoriatic lesions, natural killer and natural killer T cells appear to have a unique role. We review the evidence supporting a role for natural killer cells in psoriasis.

Preadipocyte factor-1 is associated with metabolic profile in severe obesity.

CONTEXT: Dysfunctional adipose tissue has been proposed as a key pathological process linking obesity and metabolic disease. Preadipocyte factor-1 (Pref-1) has been shown to inhibit differentiation in adipocyte precursor cells and could thereby play a role in determining adipocyte size, adipose tissue functioning, and metabolic profile in obese individuals. OBJECTIVE: We hypothesized that adipose tissue from metabolically healthy obese (MHO) and matched metabolically unhealthy obese individuals would demonstrate distinct differences in relation to Pref-1 expression, adipocyte size, and inflammatory markers. DESIGN, SETTING, AND PATIENTS: This was a cross-sectional study, investigating obese patients undergoing bariatric surgery at a tertiary referral centre. Patients included 12 MHO and 17 age- and body mass index-matched metabolically unhealthy obese individuals. MAIN OUTCOME MEASURES: Pref-1, monocyte chemotactic protein-1, TNF-α, granulocyte colony-stimulating factor, IL-6, and adiponectin levels, macrophage numbers, and adipocyte size were measured in omental and subcutaneous adipose tissue. RESULTS: The MHO group had a lower level of Pref-1 (per 1000 adipocytes) in both subcutaneous [160 (136-177) versus 194 (153-355); P < 0.05] and omental adipose tissue [102 (32-175) versus 194 (100-350); P < 0.005]. This was associated with lower numbers of macrophages, lower levels of TNF-α, monocyte chemotactic protein-1, and granulocyte colony-stimulating factor, and higher levels of adiponectin. Omental Pref-1 showed strong correlations with adipocyte size (r = 0.67, P < 0.0005) and metabolic and adipokine parameters, including percent fatty liver (r = 0.62, P < 0.005), fasting glucose (r = 0.68, P < 0.0005), triglyceride (r = 0.60, P < 0.005), high-density lipoprotein cholesterol (r = -0.46, P < 0.05), and adiponectin (r = -0.71, P < 0.05). CONCLUSION: Adipose tissue in MHO individuals had lower levels of Pref-1, a known inhibitor of preadipocyte differentiation, and a more favorable inflammatory profile. These factors may be key to protecting this subgroup of obese individuals from the adverse metabolic profile associated with excess adiposity.

The use of an intermittent terbinafine regimen for the treatment of dermatophyte toenail onychomycosis.

OBJECTIVE: To compare the efficacy and safety of intermittent terbinafine with standard courses of terbinafine and itraconazole for dermatophyte toenail onychomycosis. DESIGN: Data from a Canadian study of continuous terbinafine (CTERB) and intermittent itraconazole (III) was compared to an intermittent terbinafine regimen (TOT) using similar protocol to the randomized study. INTERVENTIONS: Terbinafine 250 mg/day for 4 weeks followed by 4 weeks of no terbinafine and then an additional 4 weeks of terbinafine 250 mg/day (TOT); terbinafine 250 mg/day for 12 weeks (CTERB); itraconazole pulse of 200 mg twice daily for 7 days on, 21 days off, three pulses given (III). RESULTS: At 72 weeks, mycological cure rates (negative KOH and culture) were 36 of 43 (83.7%), 25 of 32 (78.1%), and 17 of 30 (56.7%), for the TOT, CTERB, and III groups, respectively (P = 0.01 for TOT vs. III). Effective cure rates (simultaneous mycological cure and < or =10% nail plate involvement) were 34 of 43 (79.1%), 21 of 32 (65.6%), and 11 of 30 (36.7%), respectively (P < 0.001 for TOT vs. III; P = 0.02 for CTERB vs. III). No significant differences in effective and mycological cure rates were noted between the two terbinafine groups. Adverse events reported were similar to those reported in the respective package inserts. Most adverse events were mild to moderate, transient, and did not require interruption of the drug regimens. No serious adverse events were reported. CONCLUSIONS: A TOT intermittent terbinafine regimen provided similar efficacy and safety to the gold standard continuous terbinafine regimen and better effective cure rates than pulse itraconazole therapy.

The effects of dietary advice and vouchers on the intake of fruit and fruit juice by pregnant women in a deprived area: a controlled trial.

OBJECTIVE: To examine the effectiveness of two methods of increasing fruit and fruit juice intake in pregnancy: midwives' advice and vouchers exchangeable for juice. DESIGN: Pregnant women were randomly allocated to three groups: a control group, who received usual care; an advice group, given advice and leaflets promoting fruit and fruit juice consumption; and a voucher group, given vouchers exchangeable for fruit juice from a milk delivery firm. Dietary questionnaires were administered at ~16, 20 and 32 weeks of pregnancy. Serum beta-carotene was measured at 16 and 32 weeks. SETTING: An antenatal clinic in a deprived area. SUBJECTS: Pregnant women aged 17 years and over. RESULTS: The study comprised 190 women. Frequency of fruit consumption declined during pregnancy in all groups, but that of fruit juice increased substantially in the voucher group. Serum beta-carotene concentration increased in the voucher group, from 106.2 to 141.8 micromol l(-1) in women with measurements on both occasions (P = 0.003), decreased from 120.0 to 99.8 micromol l(-1) in the control group (P = 0.005), and was unchanged in the advice group. CONCLUSIONS: Pregnant women drink more fruit juice if they receive vouchers exchangeable for juice supplied by the milk delivery service. Midwives' advice to eat more fruit has no great effect. Providing vouchers for fruit juice is a simple method of increasing its intake in a deprived population and may be useful for other sections of the community.

Cells with haematopoietic stem cell phenotype in adult human endometrium: relevance to infertility?

BACKGROUND: Uterine lymphoid cell repertoires are specialized in order to meet the twin demands of successful pregnancy and local immunosurveillance. The possibility that some of these populations might differentiate locally from progenitor cells has been proposed. METHODS: Endometrial tissue from women with a history of infertility as well as fertile controls was examined for haematopoietic stem cells (HSCs) and lymphoid progenitors using three-colour flow cytometry. RESULTS: Significant populations of phenotypic HSCs (CD34+ CD45+ ) were detected in all samples, a high proportion of which co-expressed the differentiation marker CD45RA (45.7%), indicating ongoing differentiation. Almost 30% of uterine HSCs co-expressed CD56 and 44% co-expressed CD7, suggesting the presence of lymphoid progenitors. Small proportions expressed CD127 and CD122, receptors for interleukin (IL)-7 and IL-15, respectively. HSC numbers were similar in the endometrial samples from fertile and infertile women. However, the proportion co-expressing the natural killer (NK) antigen CD56 was significantly increased compared with HSCs found in the endometrium of fertile controls (P = 0.002). CONCLUSIONS: This is the first demonstration of cells with an HSC phenotype in the human endometrium, and increased proportions of NK progenitors in endometrium of women with infertility suggests a dysregulation of this pathway that may contribute to infertility.

Ciclopirox nail lacquer 8% for the treatment of onychomycosis: a Canadian perspective.

Onychomycosis is prevalent in the Canadian population, and risk factors, such as old age and diabetes, are increasing. This condition has traditionally been treated using oral antifungal agents with varying degrees of success. Recently, ciclopirox nail lacquer 8% solution became the first topical agent approved in Canada for onychomycosis. Ciclopirox nail lacquer may be safe and effective for the treatment of onychomycosis, and certain candidates may benefit from therapy. Ciclopirox may be implicated for prophylactic use in order to prevent recurrent infection and may be used in combination with oral agents.

Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial.

BACKGROUND: Cholinesterase inhibitors produce small improvements in cognitive and global assessments in Alzheimer's disease. We aimed to determine whether donepezil produces worthwhile improvements in disability, dependency, behavioural and psychological symptoms, carers' psychological wellbeing, or delay in institutionalisation. If so, which patients benefit, from what dose, and for how long? METHODS: 565 community-resident patients with mild to moderate Alzheimer's disease entered a 12-week run-in period in which they were randomly allocated donepezil (5 mg/day) or placebo. 486 who completed this period were rerandomised to either donepezil (5 or 10 mg/day) or placebo, with double-blind treatment continuing as long as judged appropriate. Primary endpoints were entry to institutional care and progression of disability, defined by loss of either two of four basic, or six of 11 instrumental, activities on the Bristol activities of daily living scale (BADLS). Outcome assessments were sought for all patients and analysed by logrank and multilevel models. FINDINGS: Cognition averaged 0.8 MMSE (mini-mental state examination) points better (95% CI 0.5-1.2; p<0.0001) and functionality 1.0 BADLS points better (0.5-1.6; p<0.0001) with donepezil over the first 2 years. No significant benefits were seen with donepezil compared with placebo in institutionalisation (42% vs 44% at 3 years; p=0.4) or progression of disability (58% vs 59% at 3 years; p=0.4). The relative risk of entering institutional care in the donepezil group compared with placebo was 0.97 (95% CI 0.72-1.30; p=0.8); the relative risk of progression of disability or entering institutional care was 0.96 (95% CI 0.74-1.24; p=0.7). Similarly, no significant differences were seen between donepezil and placebo in behavioural and psychological symptoms, carer psychopathology, formal care costs, unpaid caregiver time, adverse events or deaths, or between 5 mg and 10 mg donepezil. INTERPRETATION: Donepezil is not cost effective, with benefits below minimally relevant thresholds. More effective treatments than cholinesterase inhibitors are needed for Alzheimer's disease.

The relationship between postmortem urinary catecholamines, meat ultimate pH, and shear force in bulls and cows.

We investigated the relationship between stress responsiveness and meat quality in cattle. The cattle were 16-19-month-old Mixed (n=37, 303 kg) or Non-mixed (n=23, 279 kg) Friesian bulls and Friesian cull cows (1.5-7 years) that were classified Unfinished (n=133, 195 kg) or Finished for 3 months (n=34, 252 kg). A portion of m. longissimus lumborum (LL) muscle was obtained from consecutive animals for a single days slaughter of 227 cattle processed through a hot boning plant. Catecholamines were obtained from bladder urine. Ultimate pH, lactate, glycogen, glycolytic potential and representative sarcomere lengths were determined from 20-h muscle samples. Shear force measurements were from meat aged at 15 °C for 20 and 90 h. Urinary noradrenaline was similar between Mixed (14.86 ng/µmol creatinine) and Non-mixed bulls (14.07 ng/µmol creatinine) and Finished cows (15.24 ng/µmol creatinine) and elevated in the Unfinished cows (22.28 ng/µmol creatinine). Urinary adrenaline was higher in Mixed bulls (9.5 ng/µmol creatinine) than Non-mixed bulls (5.7 ng/µmol creatinine) and higher in both Unfinished cows (16.67 ng/µmol creatinine) and Finished cows (14.19 ng/µmol creatinine). For bulls that are growing well on-farm, with a only short period of fasting prior to slaughter, pH(u) is a good predictor of meat tenderness. In this situation, stressors that lower muscle glycogen pre-slaughter can have a significant effect on meat shear force, and individual animals with elevated urinary adrenaline were the most susceptible. However, in the case of cows, adrenaline responses are not necessarily associated with glycogen depletion and pH(u) is less affected than for bulls. Furthermore, the ability of meat to tenderise fully, related to reduced proteolytic turnover, is reduced in nutritionally compromised animals such as the Unfinished cows.

Difficult airway management of a child impaled through the neck.

We report the difficult airway management of a child impaled through the neck by a wooden plant support. The various options are discussed and the involvement of experienced personnel together with a clear preformulated plan of action is stressed.

Distinct ligand-binding modes for integrin alpha(v)beta(3)-mediated adhesion to fibronectin versus vitronectin.

Cell surface integrins can adopt distinct conformations in response to ligand binding and intracellular signals. Several integrins including alpha(v)beta(3) can bind to multiple ligands. The binding of alpha(v)beta(3) to fibronectin and vitronectin was used as a model to determine whether the same or distinct forms of the receptor were utilized in strong binding to the two different ligands. A spinning-disc device was used to measure the relative strength of the alpha(v)beta(3)-ligand bonds. The initial binding reaction for both ligands occurred in the absence of metabolic energy and resulted in a strong adhesion to fibronectin but a weak adhesion to vitronectin. Increases in the strength of the alpha(v)beta(3)-vitronectin bond required phosphorylation of the beta(3) cytoplasmic domain, intracellular signals, and the binding of cytoskeletal proteins to cytoplasmic domains of beta(3) controlled by Tyr-747 and Tyr-759. In contrast, alpha(v)beta(3)-mediated adhesion to fibronectin was unaffected by phorbol 12-myristate 13-acetate, mutations of Tyr-747 and Tyr-759 to phenylalanine, or availability of metabolic energy. This suggests that strong adhesion to fibronectin used the initial binding conformation, whereas strong binding to vitronectin required signaling-induced changes in the conformation of alpha(v)beta(3).