Trehalose Glycopolymer Enhances Both Solution Stability and Pharmacokinetics of a Therapeutic Protein

Biocompatible polymers such as poly(ethylene glycol) (PEG) have been successfully conjugated to therapeutic proteins to enhance their pharmacokinetics. However, many of these polymers, including PEG, only improve the in vivo lifetimes and do not protect proteins against inactivation during storage and transportation. Herein, we report a polymer with trehalose side chains (PolyProtek) that is capable of improving both the external stability and the in vivo plasma half-life of a therapeutic protein. Insulin was employed as a model biologic, and high performance liquid chromatography and dynamic light scattering confirmed that addition of trehalose glycopolymer as an excipient or covalent conjugation prevented thermal or agitation-induced aggregation of insulin. The insulin-trehalose glycopolymer conjugate also showed significantly prolonged plasma circulation time in mice, similar to the analogous insulin-PEG conjugate. The insulin-trehalose glycopolymer conjugate was active as tested by insulin tolerance tests in mice and retained bioactivity even after exposure to high temperatures. The trehalose glycopolymer was shown to be non-toxic to mice up to at least 1.6 mg/kg dosage. These results together suggest that the trehalose glycopolymer should be further explored as an alternative to PEG for long circulating protein therapeutics

Quantification of risk factors for postherpetic neuralgia in herpes zoster patients: A cohort study.

OBJECTIVE: To investigate risk factors for postherpetic neuralgia, the neuropathic pain that commonly follows herpes zoster. METHODS: Using primary care data from the Clinical Practice Research Datalink, we fitted multivariable logistic regression models to investigate potential risk factors for postherpetic neuralgia (defined as pain ≥90 days after zoster, based on diagnostic or prescription codes), including demographic characteristics, comorbidities, and characteristics of the acute zoster episode. We also assessed whether the effects were modified by antiviral use. RESULTS: Of 119,413 zoster patients, 6,956 (5.8%) developed postherpetic neuralgia. Postherpetic neuralgia risk rose steeply with age, most sharply between 50 and 79 years (adjusted odds ratio [OR] for a 10-year increase, 1.70, 99% confidence interval 1.63-1.78). Postherpetic neuralgia risk was higher in women (6.3% vs 5.1% in men: OR 1.19, 1.10-1.27) and those with severely immunosuppressive conditions, including leukemia (13.7%: 2.07, 1.08-3.96) and lymphoma (12.7%: 2.45, 1.53-3.92); autoimmune conditions, including rheumatoid arthritis (9.1%: 1.20, 0.99-1.46); and other comorbidities, including asthma and diabetes. Current and ex-smokers, as well as underweight and obese individuals, were at increased risk of postherpetic neuralgia. Antiviral use was not associated with postherpetic neuralgia (OR 1.04, 0.97-1.11). However, the increased risk associated with severe immunosuppression appeared less pronounced in patients given antivirals. CONCLUSIONS: Postherpetic neuralgia risk was increased for a number of patient characteristics and comorbidities, notably with age and among those with severe immunosuppression. As zoster vaccination is contraindicated for patients with severe immunosuppression, strategies to prevent zoster in these patients, which could include the new subunit zoster vaccine, are an increasing priority

Enhancement of Disease and Pathology by Synergy of Trichuris Suis and Campylobacter Jejuni in the Colon of Immunologically Naive Swine

Campylobacter jejuni, a leading cause of bacterial gastroenteritis, has different age distribution and disease expression in developing and developed countries, which may be due to the endemnicity of infection and the age of acquisition of immunity. Differences in disease expression are not solely dependent on the C jejuni strain or virulence attributes. Another modulating factor in developing countries may be endemic nematode infections such as Trichuris, which drive type 2 cytokine responses and down-regulate type I immune responses. In this study, three-day-old germfree pigs given dual infections with Trichuris suis and C jejuni had more frequent, more severe diarrhea and severe pathology than pigs given no pathogens, only T. suis, or only C jejuni. These pigs had significant hemorrhage and inflammatory cell infiltrates in the proximal colon where adult worms were found, and abscessed lymphoglandular complexes in the distal colon with intracellular C jejuni. Pigs given only C jejuni had mild clinical signs and pathology, and bacteria in feces or extracellular sites. Pigs given T suis or no pathogens had no disease and minimal pathology. Thus, these agents synergized to produce significant disease and pathology, which was site specific

Electronic screening for mental illness in patients with psoriasis

In this cross sectional study from a large UK centre, screening for mental illness in individuals with psoriasis has demonstrated a high burden of depression and anxiety. 85% of the cohort report that their psoriasis had affected their quality of life. Quality of life scores correlate with depression scores, emphasing the importance of managing individual's mental health alongside their psoriasis to improve overall quality of life

Factors associated with depression, anxiety, and severe mental illness among adults with atopic eczema or psoriasis: a systematic review and meta-analysis

Background: Evidence suggests an association between atopic eczema (AE) or psoriasis and mental illness. However, factors associated with mental illness are unclear. / Objectives: To synthesise and evaluate all available evidence on factors associated with depression, anxiety, and severe mental illness (SMI) among adults with AE or psoriasis. / Methods: We searched electronic databases, grey literature databases, and clinical trial registries from inception to February 2022 for studies in adults with AE or psoriasis. Eligible studies were randomised controlled trials (RCTs), cohort, cross-sectional or case-control studies where effect estimates of factors associated with depression, anxiety, or SMI were reported. We did not apply language or geographical restrictions. We assessed risk of bias using the Quality in Prognosis Studies tool. We synthesised results narratively, and if at least two studies were sufficiently homogenous, we pooled effect estimates in a random-effects meta-analysis. / Results: We included 21 studies (11 observational, 10 RCT). No observational studies in AE fulfilled our eligibility criteria. Observational studies in people with psoriasis mostly investigated factors associated with depression or anxiety – one cross-sectional study investigated factors associated with schizophrenia. Pooled effect estimates suggest being female, and psoriatic arthritis, were associated with depression (female sex:OR = 1.62,95%CI = 1.09-2.40,95%PI = 0.62-4.23, I2 = 24.90%, Tau2 = 0.05; psoriatic arthritis:OR = 2.26,95%CI = 1.56-3.25,95%PI = 0.21-24.23, I2 = 0.00%, Tau2 = 0.00) and anxiety (female sex:OR = 2.59,95%CI = 1.32-5.07,95%PI = 0.00-3956.27, I2 = 61.90%, Tau2 = 0.22; psoriatic arthritis:OR = 1.98,95%CI = 1.33-2.94, I2 = 0.00%, Tau2 = 0.00). Moderate/severe psoriasis was associated with anxiety (OR = 1.14,95%CI = 1.05-1.25, I2 = 0.00%, Tau2 = 0.00), but not depression. Evidence from RCTs suggested adults with AE or psoriasis given placebo had higher depression and anxiety scores compared to comparators given targeted treatment (e.g., biologic agents). / Conclusions: Our review highlights limited existing research on factors associated with depression, anxiety, and SMI in adults with AE or psoriasis. Observational evidence on factors associated with depression or anxiety in people with psoriasis was conflicting or from single studies, but some identified factors were consistent with those in the general population. Evidence on factors associated with SMIs in people with AE or psoriasis was particularly limited. Evidence from RCTs suggested AE and psoriasis treated with placebo was associated with higher depression and anxiety scores compared to skin disease treated with targeted therapy, however, follow-up was limited, therefore long-term effects on mental health are unclear

Risk of herpes zoster after exposure to varicella to explore the exogenous boosting hypothesis: self controlled case series study using UK electronic healthcare data.

OBJECTIVE: To assess the magnitude and duration of any hypothesised protective effect of household exposure to a child with varicella on the relative incidence of herpes zoster in adults. DESIGN: Self controlled case series. SETTING: UK general practices contributing to Clinical Practice Research Datalink. PARTICIPANTS: 9604 adults (≥18 years) with a diagnosis of herpes zoster (in primary care or hospital records) between 1997 and 2018, who during their observation period lived with a child (<18 years) with a diagnosis of varicella. MAIN OUTCOME MEASURES: Relative incidence of herpes zoster in the 20 years after exposure to a child with varicella in the household compared with baseline time (all other time, excluding the 60 days before exposure). RESULTS: 6584 of the 9604 adults with herpes zoster (68.6%) were women. Median age of exposure to a child with varicella was 38.3 years (interquartile range 32.3-48.8 years) and median observation period was 14.7 (11.1-17.7) years. 4116 adults developed zoster in the baseline period, 433 in the 60 days before exposure and 5055 in the risk period. After adjustment for age, calendar time, and season, strong evidence suggested that in the two years after household exposure to a child with varicella, adults were 33% less likely to develop zoster (incidence ratio 0.67, 95% confidence interval 0.62 to 0.73) compared with baseline time. In the 10-20 years after exposure, adults were 27% less likely to develop herpes zoster (0.73, 0.62 to 0.87) compared with baseline time. A stronger boosting effect was observed among men than among women after exposure to varicella. CONCLUSIONS: The relative incidence of zoster was lower in the periods after exposure to a household contact with varicella, with modest but long lasting protective effects observed. This study suggests that exogenous boosting provides some protection from the risk of herpes zoster, but not complete immunity, as assumed by previous cost effectiveness estimates of varicella immunisation

Partner Bereavement and Risk of Herpes Zoster: Results from Two Population-Based Case-Control Studies in Denmark and the United Kingdom.

Background: Psychological stress is commonly thought to increase the risk of herpes zoster by causing immunosuppression. However, epidemiological studies on the topic are sparse and inconsistent. We conducted 2 parallel case-control studies of the association between partner bereavement and risk of zoster using electronic healthcare data covering the entire Danish population and general practices in the UK Clinical Practice Research Datalink. Methods: We included patients with a zoster diagnosis from the primary care or hospital-based setting in 1997-2013 in Denmark (n = 190671) and 2000-2013 in the United Kingdom (n = 150207). We matched up to 4 controls to each case patient by age, sex, and general practice (United Kingdom only) using risk-set sampling. The date of diagnosis was the index date for case patients and their controls. We computed adjusted odds ratios with 99% confidence intervals for previous bereavement among case patients versus controls using conditional logistic regression with results from the 2 settings pooled using random-effects meta-analysis. Results: Overall, the adjusted odds ratios for the association between partner bereavement and zoster were 1.05 (99% confidence interval, 1.03-1.07) in Denmark and 1.01 (.98-1.05) in the United Kingdom. The pooled estimates were 0.72, 0.90, 1.10, 1.08, 1.02, 1.04, and 1.03 for bereavement within 0-7, 8-14, 15-30, 31-90, 91-365, 366-1095, and >1095 days before the index date, respectively. Conclusions: We found no consistent evidence of an increased risk of zoster after partner death. Initial fluctuations in estimates may be explained by delayed healthcare contact due to the loss

Long-term oral antibiotic use in people with acne vulgaris in UK primary care: a drug utilization study

BACKGROUND: The inappropriate use of antibiotics is understood to contribute to antimicrobial resistance. Oral antibiotics are regularly used to treat moderate-to-severe acne vulgaris. In practice, we do not know the typical length of oral antibiotic treatment courses for acne in routine primary care and what proportion of people receive more than one course of treatment following a new acne diagnosis. OBJECTIVES: To describe how oral antibiotics are prescribed for acne over time in UK primary care. METHODS: We conducted a descriptive longitudinal drug utilization study using routinely collected primary care data from the Clinical Practice Research Datalink GOLD (2004-2019). We included individuals (8-50 years) with a new acne diagnosis recorded between 1 January 2004 and 31 July 2019. RESULTS: We identified 217 410 people with a new acne diagnosis. The median age was 17 years [interquartile range (IQR) 15-25] and median follow-up was 4.3 years (IQR 1.9-7.6). Among people with a new acne diagnosis, 96 703 (44.5%) received 248 560 prescriptions for long-term oral antibiotics during a median follow-up of 5.3 years (IQR 2.8-8.5). The median number of continuous courses of antibiotic therapy (≥ 28 days) per person was four (IQR 2-6). The majority (n = 59 010, 61.0%) of first oral antibiotic prescriptions in those with a recorded acne diagnosis were between the ages of 12 and 18. Most (n = 71 544, 74.0%) first courses for oral antibiotics were for between 28 and 90 days. The median duration of the first course of treatment was 56 days (IQR 50-93 days) and 18 127 (18.7%) of prescriptions of ≥ 28 days were for < 6 weeks. Among people who received a first course of oral antibiotic for ≥ 28 days, 56 261 (58.2%) received a second course after a treatment gap of ≥ 28 days. The median time between first and second courses was 135 days (IQR 67-302). The cumulative duration of exposure to oral antibiotics during follow-up was 255 days (8.5 months). CONCLUSIONS: Further work is needed to understand the consequences of using antibiotics for shorter periods than recommended. Suboptimal treatment duration may result in reduced clinical effectiveness or repeated exposures, potentially contributing to antimicrobial resistance

Atopic Eczema in Adulthood and Risk of Depression and Anxiety: A Population-Based Cohort Study.

BACKGROUND: Atopic eczema is a common and debilitating condition associated with depression and anxiety, but the nature of this association remains unclear. OBJECTIVE: To explore the temporal relationship between atopic eczema and new depression/anxiety. METHODS: This matched cohort study used routinely collected data from the UK Clinical Practice Research Datalink, linked to hospital admissions data. We identified adults with atopic eczema (1998-2016) using a validated algorithm, and up to 5 individuals without atopic eczema matched on date of diagnosis, age, sex, and general practice. We estimated the hazard ratio (HR) for new depression/anxiety using stratified Cox regression to account for age, sex, calendar period, Index of Multiple Deprivation, glucocorticoid treatment, obesity, smoking, and harmful alcohol use. RESULTS: We identified 526,808 adults with atopic eczema who were matched to 2,569,030 without. Atopic eczema was associated with increased incidence of new depression (HR, 1.14; 99% CI, 1.12-1.16) and anxiety (HR, 1.17; 99% CI, 1.14-1.19). We observed a stronger effect of atopic eczema on depression with increasing atopic eczema severity (HR [99% CI] compared with no atopic eczema: mild, 1.10 [1.08-1.13]; moderate, 1.19 [1.15-1.23]; and severe, 1.26 [1.17-1.37]). A dose-response association, however, was less apparent for new anxiety diagnosis (HR [99% CI] compared with no atopic eczema: mild, 1.14 [1.11-1.18]; moderate, 1.21 [1.17-1.26]; and severe, 1.15; [1.05-1.25]). CONCLUSIONS: Adults with atopic eczema are more likely to develop new depression and anxiety. For depression, we observed a dose-response relationship with atopic eczema severity