Did the UK's public health shielding policy protect the clinically extremely vulnerable during the COVID-19 pandemic in Wales? Results of EVITE Immunity, a linked data retrospective study.

INTRODUCTION: The UK shielding policy intended to protect people at the highest risk of harm from COVID-19 infection. We aimed to describe intervention effects in Wales at 1 year. METHODS: Retrospective comparison of linked demographic and clinical data for cohorts comprising people identified for shielding from 23 March to 21 May 2020; and the rest of the population. Health records were extracted with event dates between 23 March 2020 and 22 March 2021 for the comparator cohort and from the date of inclusion until 1 year later for the shielded cohort. RESULTS: The shielded cohort included 117,415 people, with 3,086,385 in the comparator cohort. The largest clinical categories in the shielded cohort were severe respiratory condition (35.5%), immunosuppressive therapy (25.9%) and cancer (18.6%). People in the shielded cohort were more likely to be female, aged ≥50 years, living in relatively deprived areas, care home residents and frail. The proportion of people tested for COVID-19 was higher in the shielded cohort (odds ratio [OR] 1.616; 95% confidence interval [CI] 1.597-1.637), with lower positivity rate incident rate ratios 0.716 (95% CI 0.697-0.736). The known infection rate was higher in the shielded cohort (5.9% vs 5.7%). People in the shielded cohort were more likely to die (OR 3.683; 95% CI: 3.583-3.786), have a critical care admission (OR 3.339; 95% CI: 3.111-3.583), hospital emergency admission (OR 2.883; 95% CI: 2.837-2.930), emergency department attendance (OR 1.893; 95% CI: 1.867-1.919) and common mental disorder (OR 1.762; 95% CI: 1.735-1.789). CONCLUSION: Deaths and healthcare utilisation were higher amongst shielded people than the general population, as would be expected in the sicker population. Differences in testing rates, deprivation and pre-existing health are potential confounders; however, lack of clear impact on infection rates raises questions about the success of shielding and indicates that further research is required to fully evaluate this national policy intervention.

How point-of-care HbA1c testing changes the behaviour of people with diabetes and clinicians - a qualitative study.

AIM: To explore adults with diabetes and clinician views of point-of-care HbA1c testing. METHODS: Adults with diabetes and HbA1c ≥ 58 mmol/mol (7.5%) receiving HbA1c point-of-care testing in primary care were invited to individual interviews. Participants were interviewed twice, once prior to point-of-care testing and once after 6 months follow-up. Clinicians were interviewed once. A thematic framework based on an a priori framework was used to analyse the data. RESULTS: Fifteen participants (eight women, age range 30-70 years, two Asians, 13 white Europeans) were interviewed. They liked point-of-care testing and found the single appointment more convenient than usual care. Receiving the test result at the appointment helped some people understand how some lifestyle behaviours affected their control of diabetes and motivated them to change behaviours. Receiving an immediate test result reduced the anxiety some people experience when waiting for a result. People thought there was little value in using point-of-care testing for their annual review. Clinicians liked the point-of-care testing but expressed concerns about costs. CONCLUSIONS: This work suggests that several features of point-of-care testing may encourage behavioural change. It helped some people to link their HbA1c result to recent lifestyle behaviours, thereby motivating behavioural change and reinforcing healthy lifestyle choices.

Enhanced Power Factor and Increased Conductivity of Aluminum Doped Zinc Oxide Thin Films for Thermoelectric Applications.

We report the structural, electrical and thermopower properties of un-doped and Al doped zinc oxide (ZnO) thin films. Al doping was carried out using 25 keV Al+ implantation with 0.1, 1 and 2% Al into ZnO. X-ray diffraction measurements showed that the lattice parameters were larger than the bulk values, which is consistent with the incorporation of Al atoms at interstitials. Al doping increased the electrical conductivity from 100 (Ωcm)-1 in the un-doped ZnO film to 598 (Ωcm)-1 in the 2% Al doped ZnO film. Electron doping by Al resulted in an increase in the carrier concentration and it had an advantageous effect on the mobility where it was highest for 2% doping. The absolute value of the Seebeck coefficient systematically increased for un-doped, 1% and 2% Al doped ZnO films where the room temperature values were -50.8, -60.9 and -66.3 µV/K, respectively. The power factor increased significantly from 2.58 × 10-5 W/mK2 in un-doped ZnO film to 2.63 × 10-4 W/mK2 in 2% Al doped ZnO film. Our results suggest that the ion beam method is a suitable technique to enhance the thermoelectric properties of ZnO.

The development of inter-strain variation in cortical and trabecular traits during growth of the mouse lumbar vertebral body.

How cortical and trabecular bone co-develop to establish a mechanically functional structure is not well understood. Comparing early postnatal differences in morphology of lumbar vertebral bodies for three inbred mouse strains identified coordinated changes within and between cortical and trabecular traits. These early coordinate changes defined the phenotypic differences among the inbred mouse strains. INTRODUCTION: Age-related changes in cortical and trabecular traits have been well studied; however, very little is known about how these bone tissues co-develop from day 1 of postnatal growth to establish functional structures by adulthood. In this study, we aimed to establish how cortical and trabecular tissues within the lumbar vertebral body change during growth for three inbred mouse strains that express wide variation in adult bone structure and function. METHODS: Bone traits were quantified for lumbar vertebral bodies of female A/J, C57BL/6J (B6), and C3H/HeJ (C3H) inbred mouse strains from 1 to 105 days of age (n = 6-10 mice/age/strain). RESULTS: Inter-strain differences in external bone size were observed as early as 1 day of age. Reciprocal and rapid changes in the trabecular bone volume fraction and alignment in the direction of axial compression were observed by 7 days of age. Importantly, the inter-strain difference in adult trabecular bone volume fraction was established by 7 days of age. Early variation in external bone size and trabecular architecture was followed by progressive increases in cortical area between 28 and 105 days of age, with the greatest increases in cortical area seen in the mouse strain with the lowest trabecular mass. CONCLUSION: Establishing the temporal changes in bone morphology for three inbred mouse strains revealed that genetic variation in adult trabecular traits were established early in postnatal development. Early variation in trabecular architecture preceded strain-specific increases in cortical area and changes in cortical thickness. This study established the sequence of how cortical and trabecular traits co-develop during growth, which is important for identifying critical early ages to further focus on intervention studies that optimize adult bone strength.

Delusional infestation may be caused by recreational drug usage in some patients, but they may not disclose their habit.

BACKGROUND: Patients with delusional infestation (DI) believe that their skin is infested with organisms or inanimate particles, despite objective evidence to the contrary. Previous studies indicate a higher rate of recreational drug use among patients with DI. It is known that symptoms of infestation such as formication can be secondary to use of recreational drugs and alcohol. We carried out a pilot study observing the prevalence of recreational drug use in patients with DI. AIM: To observe the prevalence of recreational drug use in patients with DI. METHODS: A retrospective review of 86 consecutive patient records was carried out over a 3-year period (1 March 2012 to 1 March 2015) to determine current or previous recreational drug use. Additionally, 24 consecutive patients with DI attending clinic between 1 December 2014 and 1 March 2015 were prospectively offered a urine test for recreational drugs. RESULTS: Of the 86 patients, 19 had recreational drug use documented in their medical notes (22.1%). Of the 24 patients offered a urine test, 18 accepted (75%); the remaining 6 patients agreed to provide a urine sample immediately after consultation, but did not do so. Of the 18 samples collected, 6 were positive (33.3% of completed tests) for recreational drugs. Cannabis was the most commonly used drug. CONCLUSIONS: This study indicates that the prevalence of recreational drug use in patients with DI is high, and that patients do not always disclose their habit. It is hoped that this pilot study will lead to further research into this finding.

Comparison of cold knife cone biopsy and loop electrosurgical excision procedure in the management of cervical adenocarcinoma in situ: What is the gold standard?

OBJECTIVE: To compare the outcomes of patients with cervical adenocarcinoma in situ (ACIS) treated with cold knife cone (CKC) biopsy or loop electrosurgical excision procedure (LEEP) for the treatment of cervical adenocarcinoma in situ (ACIS). STUDY DESIGN: This is a retrospective, population-based cohort study of Western Australian patients with ACIS diagnosed between 2001 and 2012. Outcomes included pathological margin status and the incidence of persistent or recurrent endocervical neoplasia (ACIS and adenocarcinoma) during follow-up (<12 months) and surveillance (≥12 months) periods. RESULTS: The study group comprised 338 patients including 107 (32%) treated initially by LEEP and 231 (68%) treated by CKC biopsy. The mean age was 33.2 years (range 18 to 76 years) and median follow-up interval was 3.6 years (range <1 year to 11.8 years). Overall, 27 (8.0%) patients had ACIS persistence/recurrence while 9 (2.7%) were diagnosed with adenocarcinoma during the follow-up and surveillance periods. No patient died of cervical cancer within the study period. There were no significant differences in the incidence of persistent and/or recurrent endocervical neoplasia according to the type of excisional procedure. Patients with positive biopsy margins were 3.4 times more likely to have disease persistence or recurrence. CONCLUSION(S): LEEP and CKC biopsy appear equally effective in the treatment of ACIS for women wishing to preserve fertility. Patients undergoing conservative management for ACIS should be closely monitored, particularly if biopsy margins are positive in initial excision specimens. Patients and their clinicians should be aware of the potential risks of residual and recurrent disease.

Multiple vitellogenins and product yolk proteins in striped bass, Morone saxatilis: molecular characterization and processing during oocyte growth and maturation.

The multiple vitellogenin (Vtg) system of striped bass, a perciform species spawning nearly neutrally buoyant eggs in freshwater, was investigated. Vitellogenin cDNA cloning, Western blotting of yolk proteins (YPs) using Vtg and YP type-specific antisera, and tandem mass spectrometry (MS/MS) of the YPs revealed the complex mechanisms of yolk formation and maturation in this species. It was discovered that striped bass possesses a tripartite Vtg system (VtgAa, VtgAb, and VtgC) in which all three forms of Vtg make a substantial contribution to the yolk. The production of Vtg-derived YPs is generally similar to that described for other perciforms. However, novel amino-terminal labeling of oocyte YPs prior to MS/MS identified multiple alternative sites for cleavage of these proteins from their parent Vtg, revealing a YP mixture far more complex than reported previously. This approach also revealed that the major YP product of each form of striped bass Vtg, lipovitellin heavy chain (LvH), undergoes limited degradation to smaller polypeptides during oocyte maturation, unlike the case in marine fishes spawning buoyant eggs in which LvHAa undergoes extensive proteolysis to osmotically active free amino acids. These differences likely reflect the lesser need for hydration of pelagic eggs spawned in freshwater. The detailed characterization of Vtgs and their proteolytic fate(s) during oocyte growth and maturation establishes striped bass as a freshwater model for investigating teleost multiple Vtg systems.

Utility of healthcare-worker-targeted antimicrobial stewardship interventions in hospitals of low- and lower-middle-income countries: a scoping review of systematic reviews.

BACKGROUND: Antimicrobial stewardship (AMS) initiatives in hospitals often include the implementation of clustered intervention components to improve the surveillance and targeting of antibiotics. However, impacts of the individual components of AMS interventions are not well known, especially in low- and lower-middle-income countries (LLMICs). OBJECTIVE: A scoping review was conducted to summarize evidence from systematic reviews (SRs) on the impact of common hospital-implemented healthcare-worker-targeted components of AMS interventions that may be appropriate for LLMICs. METHODS: Major databases were searched systematically for SRs of AMS interventions that were evaluated in hospitals. For SRs to be eligible, they had to report on at least one intervention that could be categorized according to the Effective Practice and Organisation of Care taxonomy. Clinical and process outcomes were considered. Primary studies from LLMICs were consulted for additional information. RESULTS: Eighteen SRs of the evaluation of intervention components met the inclusion criteria. The evidence shows that audit and feedback, and clinical practice guidelines improved several clinical and process outcomes in hospitals. An unintended consequence of interventions was an increase in the use of antibiotics. There was a cumulative total of 547 unique studies, but only 2% (N=12) were conducted in hospitals in LLMICs. Two studies in LLMICs reported that guidelines and educational meetings were effective in hospitals. CONCLUSION: Evidence from high- and upper-middle-income countries suggests that audit and feedback, and clinical practice guidelines have the potential to improve various clinical and process outcomes in hospitals. The lack of evidence in LLMIC settings prevents firm conclusions from being drawn, and highlights the need for further research.

Cooperation between Shh and IGF-I in promoting myogenic proliferation and differentiation via the MAPK/ERK and PI3K/Akt pathways requires Smo activity.

Sonic Hedgehog (Shh) has been shown to promote adult myoblast proliferation and differentiation and affect Akt phosphorylation via its effector Smoothened (Smo). Here, the relationship between Shh and insulin-like growth factor I (IGF-I) was examined with regard to myogenic differentiation via signaling pathways which regulate this process. Each factor enhanced Akt and MAPK/ERK (p42/44) phosphorylation and myogenic factor expression levels in a dose-responsive manner, while combinations of Shh and IGF-I showed additive effects. Blockage of the IGF-I effects by neutralizing antibody partially reduced Shh's effects on signaling pathways, suggesting that IGF-I enhances, but is not essential for Shh effects. Addition of cyclopamine, a Smo inhibitor, reduced Shh- and IGF-I-induced Akt phosphorylation in a similar manner, implying that Shh affects gain of the IGF-I signaling pathway. This implication was also examined via a genetic approach. In cultures derived from Smo(mut) (MCre;Smo(flox/flox)) mice lacking Smo expression specifically in hindlimb muscles, IGF-I-induced Akt and p42/44 phosphorylation was significantly reduced compared to IGF-I's effect on Smo(cont) cells. Moreover, remarkable inhibition of the stimulatory effect of IGF-I on myogenic differentiation was observed in Smo(mut) cultures, implying that intact Smo is required for IGF-I effects in myoblasts. Immunoprecipitation assays revealed that tyrosine-phosphorylated proteins, including the regulatory unit of PI3K (p85), are recruited to Smo in response to Shh. Moreover, IGF-IR was found to associate with Smo in response to Shh and to IGF-I, suggesting that Shh and IGF-I are already integrated at the receptor level, a mechanism by which their signaling pathways interact in augmenting their effects on adult myoblasts.

Large hepatitis delta antigen activates STAT-3 and NF-κB via oxidative stress.

Hepatitis delta virus (HDV) coinfection or superinfection in hepatitis B virus (HBV)-infected patients results in a more aggressive liver disease, with more often fulminant forms and more rapid progression to cirrhosis and hepatocellular carcinoma. The mechanism(s) for this pejorative evolution remains unclear. To explore a specific HDV pathogenesis, we used a model of transient transfection of plasmids expressing the small (sHDAg or p24) or the large (LHDAg or p27) delta antigen in hepatocyte cell lines. We found that the production of reactive oxygen species was significantly higher in cells expressing p27. Consequently, p27 activated the signal transducer and activator of transcription-3 (STAT-3) and the nuclear factor kappa B (NF-κB) via the oxidative stress pathway. Moreover in the presence of antioxidants (PDTC, NAC) or calcium inhibitors (TMB-8, BAPTA-AM, Ruthenium Red), p27-induced activation of STAT-3 and NF-κB was dramatically reduced. Similarly, using a mutated form of p27, where the cysteine 211-isoprenylation residue was replaced by a serine, a significant reduction of STAT-3 and NF-κB activation was seen, suggesting the involvement of isoprenylation in this process. Additionally, we show that p27 is able to induce oxidative stress through activation of NADPH oxidase-4. These results provide insight into the mechanisms by which p27 can alter intracellular events relevant to HDV-related liver pathogenesis.

Prevalence of bacterial burden on macroscopic contaminants of orthopaedic surgical instruments following sterilization.

BACKGROUND: Macroscopic contamination of orthopaedic instruments with particulates, including cortical bone and polymethyl methacrylate (PMMA) bone cement, that have previously undergone pre-operative sterilization is frequently encountered peri- or intraoperatively, calling into question the sterility of such instruments. AIM: To determine if macroscopic contaminants of orthopaedic surgical instrumentation maintain a bacterial burden following sterile processing, and to determine the most commonly contaminated instruments and the most common contaminants. METHODS: Macroscopic contaminants in orthopaedic instrument trays were collected prospectively at a single tertiary referral centre over a 6-month period from August 2021 to May 2022. When identified, these specimens were swabbed and plated on sheep blood agar. All specimens were incubated at 37 °C for 14 days, and inspected visually for colony formation. When bacterial colony formation was identified, samples were sent for species identification. RESULTS: In total, 33 contaminants were tested, and only one contaminant was found to be growing bacterial colonies (Corynebacterium sp.). The items most commonly found to have macroscopic contamination were surgical trays (N=9) and cannulated drills (N=7). The identifiable contaminants were bone (N=10), PMMA bone cement (N=4) and hair (N=4). Eleven macroscopic contaminants were not identifiable. CONCLUSION: This study found that 97% of macroscopic orthopaedic surgical instrument contaminants that underwent sterile processing did not possess a bacterial burden. Contaminants discovered during a procedure are likely to be sterile, and do not pose a substantially increased risk of infection to a patient.

Phylogeography of the Afromontane Prunus africana reveals a former migration corridor between East and West African highlands.

Scattered populations of the same tree species in montane forests through Africa have led to speculations on the origins of distributions. Here, we inferred the colonization history of the Afromontane tree Prunus africana using seven chloroplast DNA loci to study 582 individuals from 32 populations sampled in a range-wide survey from across Africa, revealing 22 haplotypes. The predominant haplotype, HT1a, occurred in 13 populations of eastern and southern Africa, while a second common haplotype, HT1m, occurred in populations of western Uganda and western Africa. The high differentiation observed between populations in East Africa was unexpected, with stands in western Uganda belonging with the western African lineage. High genetic differentiation among populations revealed using ordered alleles (N(ST) = 0.840) compared with unordered alleles (G(ST) = 0.735), indicated a clear phylogeographic pattern. Bayesian coalescence modelling suggested that 'east' and 'west' African types likely split early during southward migration of the species, while further more recent splitting events occurred among populations in the East of the continent. The high genetic similarity found between western Uganda and west African populations indicates that a former Afromontane migration corridor may have existed through Equatorial Africa.

Differential corticospinal tract degeneration in homozygous 'D90A' SOD-1 ALS and sporadic ALS.

BACKGROUND: The homogeneous genotype and stereotyped phenotype of a unique familial form of amyotrophic lateral sclerosis (ALS) (patients homozygous for aspartate-to-alanine mutations in codon 90 (homD90A) superoxide dismutase 1) provides an ideal model for studying genotype/phenotype interactions and pathological features compared with heterogeneous apparently sporadic ALS. The authors aimed to use diffusion tensor tractography to quantify and compare changes in the intracerebral corticospinal tracts of patients with both forms of ALS, building on previous work using whole-brain voxelwise group analysis. METHOD: 21 sporadic ALS patients, seven homD90A patients and 20 healthy controls underwent 1.5 T diffusion tensor MRI. Patients were assessed using 'upper motor neuron burden,' El Escorial and ALSFR-R scales. The intracranial corticospinal tract was assessed using diffusion tensor tractography measures of fractional anisotropy (FA), mean diffusivity, and radial and axial diffusivity obtained from its entire length. RESULTS: Corticospinal tract FA was reduced in sporadic ALS patients compared with both homD90A ALS patients and controls. The diffusion measures in sporadic ALS patients were consistent with anterograde (Wallerian) degeneration of the corticospinal tracts. In sporadic ALS, corticospinal tract FA was related to clinical measures. Despite a similar degree of clinical upper motor neuron dysfunction and disability in homD90A ALS patients compared with sporadic ALS, there were no abnormalities in corticospinal tract diffusion measures compared with controls. CONCLUSIONS: Diffusion tensor tractography has shown axonal degeneration within the intracerebral portion of the corticospinal tract in sporadic ALS patients, but not those with a homogeneous form of familial ALS. This suggests significant genotypic influences on the phenotype of ALS and may provide clues to slower progression of disease in homD90A patients.

Healthcare-associated infections and the prescribing of antibiotics in hospitalized patients of the Caribbean Community (CARICOM) states: a mixed-methods systematic review.

BACKGROUND: Healthcare-associated infections (HCAIs) and variation in antibiotic prescribing pose a significant public health challenge in hospitals of low-resource countries. AIM: To critically appraise and synthesize the evidence on HCAI and the prescribing of antibiotics in Caribbean Community (CARICOM) states. METHODS: All primary qualitative and quantitative studies that addressed HCAI, and the prescribing of antibiotics in hospitalized patients of CARICOM states were included. Ovid Medline, Embase, Global Health, and regional databases were searched. Risk of bias was assessed using the Mixed Methods Appraisal Tool. Findings were presented in narrative and table formats. FINDINGS: Twenty-one studies met the inclusion criteria for this mixed-methods systematic review (MMSR). Studies were from four different CARICOM states: Trinidad and Tobago, Jamaica, Haiti, and Antigua and Barbuda. Intensive care units (ICUs) had the highest rate of infections (67% over four years). Surgical site infections were discussed by seven studies and ranged from 1.5% to 7.3%. For inpatients with contaminated or infected wounds, rates ranged from 29% to 83%. Empiric and prophylactic therapies were common and inappropriately prescribed. Resources and training for healthcare workers in infection control and antimicrobial stewardship were insufficient. Few qualitative studies existed, so it was not possible to integrate evidence from qualitative and quantitative paradigms. CONCLUSION: Evidence from CARICOM states shows high rates of HCAI and inappropriately prescribed antibiotics, primarily in ICUs. Disease surveillance, infection control, and antimicrobial stewardship programmes require urgent evidence-based improvements.

Fluvastatin and lovastatin inhibit granulocyte macrophage-colony stimulating factor-stimulated human eosinophil adhesion to inter-cellular adhesion molecule-1 under flow conditions.

BACKGROUND: Eosinophil accumulation in the lung is an important feature of airway inflammation in asthma. There is therefore much interest in developing novel therapies to prevent this process. Accumulating evidence suggests that statins have anti-inflammatory properties, including inhibition of leucocyte accumulation. We therefore assessed the ability of five statins to inhibit human eosinophil adhesion to recombinant human inter-cellular adhesion molecule (rhICAM)-1 under physiologically relevant flow conditions. METHODS: Purified eosinophils were pre-treated with a panel of statins before elucidation of the adhesion profiles of resting and granulocyte macrophage-colony stimulating factor (GM-CSF)-stimulated cells to rhICAM-1-coated microchannels at a flow rate of 0.5 dynes/cm(2). Images were recorded in real-time at 1 min intervals and analysed using Ducocell software. RESULTS: Fluvastatin and lovastatin (both 10 nm) significantly inhibited GM-CSF-stimulated eosinophil adhesion to rhICAM-1 after 2 min (34.4+/-3.0% inhibition and 37.8+/-12.6% inhibition, respectively, n=4, P<0.05) but had no significant inhibitory effect on unstimulated eosinophil adhesion. Mevastatin, simvastatin, and pravastatin (all 10 nm) had no significant effect on GM-CSF-stimulated eosinophil adhesion to rhICAM-1. A concentration range of fluvastatin and lovastatin inhibited GM-CSF stimulated eosinophil adhesion with significant (P<0.05) inhibition observed at low concentrations of 1 nm for both drugs. Mevalonate (100 nm) reversed fluvastatin-mediated but not lovastatin-mediated inhibition of eosinophil adhesion. CONCLUSIONS: Inhibition of eosinophil adhesion to ICAM-1 by fluvastatin and lovastatin under physiological shear stress represent novel actions by these drugs that may inform the development of anti-inflammatory therapy for allergic disease.

1,25-dihydroxycholecalciferol: identification of the proposed active form of vitamin D3 in the intestine.

The major polar metabolite of cholecalciferol (vitamin D(3)) present in chick intestinal mucosa has been chemically characterized by mass spectrometric analysis to have a molecular formula of C(27)H(44)0(3) and a structure of 1,25-dihydroxycholecalciferol. This compound, which is produced in the kidney from 25-hydroxycholecalciferol, has been previously shown to be from 4 to 13 times as active as cholecalciferol in stimulating intestinal calcium transport. 1,25-Dihydroxycholecalciferol (previously designated metabolite 4B in this (laboratory) probably represents the biologically active form of cholecalciferol in the intestine.