Impact of oral abrocitinib on signs, symptoms and quality of life among adolescents with moderate-to-severe atopic dermatitis: an analysis of patient-reported outcomes.

BACKGROUND: A significant improvement in clinical signs was demonstrated with abrocitinib relative to placebo in adolescents with moderate-to-severe atopic dermatitis (AD) in three phase 3, randomized, double-blinded, placebo-controlled studies (JADE TEEN [ClinicalTrials.gov, NCT03796676], JADE MONO-1 [NCT03349060] and JADE MONO-2 [NCT03575871]). OBJECTIVES: To evaluate the impact of abrocitinib on patient-reported signs/symptoms, including sleep loss and quality of life among adolescents with moderate-to-severe AD. METHODS: JADE TEEN, JADE MONO-1 and JADE MONO-2 were conducted in the Asia-Pacific region, Europe and North America and included patients aged 12-17 years with moderate-to-severe AD and inadequate response to ≥ 4 consecutive weeks of topical medication or treatment with systemic therapy for AD. Patients were randomly assigned (1 : 1 : 1, JADE TEEN; 2 : 2 : 1, JADE MONO-1/-2) to receive once-daily oral abrocitinib (200 or 100 mg) or placebo for 12 weeks in combination with topical therapy (JADE TEEN) or as monotherapy (JADE MONO-1/-2). Data from adolescent patients in JADE MONO-1/-2 were pooled for these analyses. RESULTS: At week 12, more adolescents treated with abrocitinib (200 or 100 mg) vs. placebo achieved a ≥ 4-point improvement from baseline in the Patient-Oriented Eczema Measure in JADE TEEN (83.9% and 77.0% vs. 60.2%) and JADE MONO-1/-2 (83.0% and 69.4% vs. 43.5%) and a ≥ 6-point improvement from baseline in the Children's Dermatology Life Quality Index in JADE TEEN (73.8% and 67.5% vs. 56.5%) and JADE MONO-1/-2 (70.0% and 57.1% vs. 19.0%). Significant improvements in SCORing Atopic Dermatitis Visual Analog Scale for sleep loss scores were demonstrated with abrocitinib vs. placebo at weeks 2-12 in JADE TEEN and JADE MONO-1/-2. CONCLUSIONS: Patient-reported signs/symptoms, including reduction of sleep loss and quality of life, were substantially improved with abrocitinib monotherapy or combination therapy relative to placebo in adolescents with moderate-to-severe AD.

Guidelines for clinical trials of frontal fibrosing alopecia: consensus recommendations from the International FFA Cooperative Group (IFFACG).

BACKGROUND: Frontal fibrosing alopecia (FFA) has become one of the most common causes of cicatricial alopecia worldwide. However, there is a lack of clear aetiology and robust clinical trial evidence for the efficacy and safety of agents currently used for treatment. OBJECTIVES: To enable data to be collected worldwide on FFA using common criteria and assessment methods. METHODS: A multicentre, international group of experts in hair loss was convened by email to create consensus recommendations for clinical trials. Consensus was defined at > 90% agreement on each recommended part of these guidelines. RESULTS: Standardized diagnostic criteria, severity rating, staging, and investigator and patient assessment of scalp hair loss and other clinical features of FFA were created. CONCLUSIONS: These guidelines should allow the collection of reliable aggregate data on FFA and advance efforts in both clinical and basic research to close knowledge gaps in this condition.

Anticholinergic drug use and risk of mortality for people with dementia in Northern Ireland.

OBJECTIVE: Anticholinergic burden refers to the cumulative effect of medications which contain anticholinergic properties. We assessed how anticholinergic burden and different types of anticholinergic medications influence mortality rates among people with dementia in Northern Ireland. Our secondary aim was to determine what demographic characteristics predict the anticholinergic burden of people with dementia. METHODS: Data were extracted from the Enhanced Prescribing database for 25,418 people who were prescribed at least one dementia management medication between 2010 and 2016. Information was also extracted on the number of times each available anticholinergic drug was prescribed between 2010 and 2016, allowing the calculation of an overall anticholinergic burden. Cox proportional hazard models were used to determine how anticholinergic burden influenced mortality whilst multilevel model regression determined what demographic characteristics influence overall anticholinergic burden. RESULTS: Of the 25,418 people with dementia, only 15% (n = 3880) had no anticholinergic burden. Diazepam (42%) and risperidone (18%) were the two most commonly prescribed drugs. Unadjusted Cox proportional hazard models indicated that higher anticholinergic burden was associated with significantly higher mortality rates in comparison to people with dementia who had no anticholinergic burden (HR = 1.59: 95% CI = 1.07-2.36). In particular, urological (HR = 1.20: 95% CI = 1.05-1.38) and respiratory (HR = 1.17: 95% CI = 1.08-1.27) drugs significantly increased mortality rates. People with dementia living in areas with low levels of deprivation had significantly lower anticholinergic burden (HR=-.39: 95% CI=-.47:-30). CONCLUSIONS: Reducing anticholinergic burden is essential for people with dementia. Further research should address the unfavourable prognosis of people living with dementia in highly deprived areas.

Pseudofolliculitis barbae: understanding the condition and the role of facial grooming.

Pseudofolliculitis barbae (PFB) is an inflammatory condition of the beard area, with a high prevalence in men of subequatorial African ancestry and, to a much lesser extent, Indo-Europeans. But it can affect both men and women of all ethnicities. Invariably reported as being associated with shaving, recent evidence suggests a strong genetic component in patients with persistent PFB. There is a lack of robust clinical evidence to support recommendations to avoid or curtail shaving or to shave with a single-blade razor. There is recent clinical evidence that PFB is not exacerbated by daily shaving with a multiblade razor as part of a regimen. Further, there is preliminary evidence that a daily shaving regimen, which includes pre-shave hydration and post-shave moisturization, may be beneficial. To develop evidence-based initial management strategies for PFB, there is a requirement for more randomized blinded clinical trials comparing the use of multi- and single-edge razors, different shaving techniques, shaving frequencies and pre- and post-shaving cosmetic products.

Climate change, food systems and population health risks in their eco-social context.

The establishment of ecological public health as crucial to modern public health is overdue. While the basic concepts have been gestating for decades, receptivity within broader public health has been limited. This position is changing, not least as the population-level impacts of climate change and, more broadly, of limits to growth are emerging from theory and forecasting into daily reality. This paper describes several key elements of ecological public health thinking. These include the 'environmental' risks to human health (often systemic and disruptive, rather than local and toxic) posed by climate change and other forms of adverse global environmental change. Closer recognition of the links between social and environmental factors has been urged--an 'eco-social' approach--and, relatedly, for greater co-operation between social and natural sciences. The authors revisit critics of capitalism who foresaw the global capture and transformation of ecosystems for material human ends, and their resultant despoliation. The perennial call within public health to reduce vulnerability by lessening poverty is more important than ever, given the multifactored threat to the health of the poor which is anticipated, assuming no radical strategies to alleviate these pressures. But enhanced health security for the poor requires more than the reconfiguring of social determinants; it also requires, as the overarching frame, ecological public health.

Hospital admissions and emergency department visits for people with dementia.

BACKGROUND: Previous studies have suggested that people with dementia (PwD) are more likely to be admitted to hospital, have prolonged hospital stay, or visit an emergency department (ED), compared to people without dementia. AIM: This study assessed the rates of hospital admissions and ED visits in PwD and investigated the causes and factors predicting this healthcare use. Further, this study assessed survival following hospital admissions and ED visits. DESIGN: This was a retrospective study with data from 26 875 PwD and 23 961 controls. METHODS: Data from national datasets were extracted for demographic characteristics, transitions to care homes, hospital and ED use and were linked through the Honest Broker Service. PwD were identified through dementia medication and through causes for hospital admissions and death. RESULTS: Dementia was associated with increased risk of hospital admissions and ED visits, and with lower odds of hospital readmission. Significant predictors for hospital admissions and readmissions in PwD were transitioning to a care home, living in urban areas and being widowed, while female gender and living in less deprived areas reduced the odds of admissions. Older age and living in less deprived areas were associated with lower odds of an ED visit for PwD. In contrast to predictions, mortality rates were lower for PwD following a hospital admission or ED visit. CONCLUSIONS: These findings result in a better understanding of hospital and ED use for PwD. Surprisingly, survival for PwD was prolonged following hospital admissions and ED visits and thus, policies and services enabling these visits are necessary, especially for people who live alone or in rural areas; however, increased primary care and other methods, such as eHealth, could provide equally effective care in order to avoid distress and costs for hospital admissions and ED visits.

Occupational exposure and risk of central nervous system demyelination.

Inconsistent evidence exists regarding the association between work-related factors and risk of multiple sclerosis (MS). We examined the association between occupational exposures and risk of a first clinical diagnosis of central nervous system demyelination (FCD), which is strongly associated with progression to MS, in a matched case-control study of 276 FCD cases and 538 controls conducted in Australia (2003-2006). Using a personal residence and work calendar, information on occupational history and exposure to chemicals and animals was collected through face-to-face interviews. Few case-control differences were noted. Fewer cases had worked as professionals (≥6 years) than controls (adjusted odds ratio (AOR) = 0.60, 95% confidence interval (CI): 0.37, 0.96). After further adjustment for number of children, cases were more likely to have ever been exposed to livestock than controls (AOR = 1.54, 95% CI: 1.03, 2.29). Among women, there was an increase in FCD risk associated with 10 or more years of exposure to livestock (AOR = 2.78, 95% CI: 1.22, 6.33) or 6 or more years of farming (AOR = 2.00, 95% CI: 1.23, 3.25; also adjusted for number of children). Similar findings were not evident among men. Thus, farming and exposure to livestock may be important factors in the development of FCD among women, with this finding further revealed after the confounding effect of parity or number of children is considered.

The AusD Study: a population-based study of the determinants of serum 25-hydroxyvitamin D concentration across a broad latitude range.

Observational studies suggest that people with a high serum 25-hydroxyvitamin D (25(OH)D) concentration may have reduced risk of chronic diseases such as osteoporosis, multiple sclerosis, type 1 diabetes, cardiovascular disease, and some cancers. The AusD Study (A Quantitative Assessment of Solar UV Exposure for Vitamin D Synthesis in Australian Adults) was conducted to clarify the relationships between ultraviolet (UV) radiation exposure, dietary intake of vitamin D, and serum 25(OH)D concentration among Australian adults residing in Townsville (19.3°S), Brisbane (27.5°S), Canberra (35.3°S), and Hobart (42.8°S). Participants aged 18-75 years were recruited from the Australian Electoral Roll between 2009 and 2010. Measurements were made of height, weight, waist:hip ratio, skin, hair, and eye color, blood pressure, and grip strength. Participants completed a questionnaire on sun exposure and vitamin D intake, together with 10 days of personal UV dosimetry and an associated sun-exposure and physical-activity diary that was temporally linked to a blood test for measurement of 25(OH)D concentration. Ambient solar UV radiation was also monitored at all study sites. We collected comprehensive, high-quality data from 1,002 participants (459 males, 543 females) assessed simultaneously across a range of latitudes and through all seasons. Here we describe the scientific and methodological issues considered in designing the AusD Study.

Early-life hygiene-related factors affect risk of central nervous system demyelination and asthma differentially.

The increasing prevalence of immune-related diseases, including multiple sclerosis, may be partly explained by reduced microbial burden during childhood. Within a multi-centre case-control study population, we examined: (i) the co-morbid immune diseases profile of adults with a first clinical diagnosis of central nervous system demyelination (FCD) and (ii) sibship structure in relation to an autoimmune (FCD) and an allergic (asthma) disease. FCD cases (n = 282) were aged 18-59 years; controls (n = 558) were matched on age, sex and region. Measures include: history of doctor-diagnosed asthma; sibling profile (number; dates of birth); and regular childcare attendance. FCD cases did not differ from controls with regard to personal or family history of allergy, but had a greater likelihood of chronic fatigue syndrome [odds ratio (OR) = 3·11; 95% confidence interval (CI) 1·11, 8·71]. Having any younger siblings showed reduced odds of FCD (OR = 0·68; 95% CI: 0·49, 0·95) but not asthma (OR = 1·47; 95% CI: 0·91, 2·38). In contrast, an increasing number of older siblings was associated with reduced risk of asthma (P trend = 0·04) but not FCD (P trend = 0·66). Allergies were not over-represented among people presenting with FCD. Sibship characteristics influence both FCD and asthma risk but the underlying mechanisms differ, possibly due to the timing of the putative 'sibling effect'.

Central centrifugal cicatricial alopecia severity is associated with cowhage-induced itch.

BACKGROUND: Patients with central centrifugal cicatricial alopecia (CCCA) often suffer from varying degrees of itch, pain and burning sensations. However, the neural component of these skin sensations has not been assessed. OBJECTIVE: To conduct a comprehensive analysis of C nerve fibre function relating to itch and pain perception in patients with CCCA using thermosensory testing and experimental itch models. METHODS: Fifteen healthy African-American women and 16 African-American female patients with CCCA participated in the study and underwent quantitative computerized thermosensory testing to assess warmth and heat pain thresholds. Itch was induced using histamine iontophoresis and application of cowhage spicules, and the intensity of each itch was assessed. The association between itch intensity and CCCA severity score was examined. RESULTS: A positive correlation between CCCA severity score and peak itch ratings of cowhage on the lesional scalp (crown) was observed (P = 0·023, r = 0·562). Notably, the histamine peak itch rating was not found to have a significant correlation with CCCA severity score (P = 0·913). The crown also had significantly higher warmth and pain thresholds than the occiput in both healthy subjects and patients with CCCA. CONCLUSIONS: Our results suggest a putative role for the protease-activated receptor (PAR)-2, which is activated by cowhage, in the pathogenesis of CCCA. Future studies should examine PAR-2-directed therapeutics for patients with CCCA. Examining for itch and other dysaesthesias in patients with CCCA is of vital importance to dermatologists in assessing disease severity.

Aberrant C nerve fibre function of the healthy scalp.

BACKGROUND: The scalp is commonly associated with itch and burning sensations. Previous studies have shown the scalp is highly innervated compared with other body areas. However, limited data are available on sensory testing associated with C nerve fibres of the healthy scalp. OBJECTIVE: To examine the function of C nerve fibre-mediated sensations such as warmth, heat pain, itch and neurogenic inflammation in two areas of the scalp (crown and occiput) in comparison to forearm skin. METHODS: Twenty-two healthy subjects (11 women, 11 men) underwent quantitative computerized thermosensory testing to assess warmth and heat pain thresholds. Itch was induced using histamine iontophoresis and application of cowhage spicules, and the intensity of each itch was assessed. Skin blood flow was measured at baseline and after each itch induction to assess degree of neurogenic inflammation. RESULTS: A majority (64%) of the crown warmth threshold measurements exceeded 50°C while all 22 forearm warmth thresholds measurements were significantly lower than 50°C. Both scalp sites had significantly higher warmth and heat pain thresholds compared with the forearm (P<0·001). Itch ratings of histamine and cowhage on both scalp sites were significantly lower than on the forearm (P≤0·001). Histamine and cowhage induced an increase in skin blood flow from baseline on the forearm compared with the scalp (P< 0·001). CONCLUSIONS: This study demonstrates a significant insensitivity of C nerve fibres of the scalp to warmth, heat pain, itch and neurogenic inflammation. These results suggest that the scalp has an aberrant response of C nerve fibres.

Climate change: present and future risks to health, and necessary responses.

Recent observed changes in Earth's climate, to which humans have contributed substantially, are affecting various health outcomes. These include altered distributions of some infectious disease vectors (ticks at high latitudes, malaria mosquitoes at high altitudes), and an uptrend in extreme weather events and associated deaths, injuries and other health outcomes. Future climate change, if unchecked, will have increasing, mostly adverse, health impacts - both direct and indirect. Climate change will amplify health problems in vulnerable regions, influence infectious disease emergence, affect food yields and nutrition, increase risks of climate-related disasters and impair mental health. The health sector should assist society understand the risks to health and the needed responses.

Promoting global population health while constraining the environmental footprint.

Populations today face increasing health risks from human-induced regional and global environmental changes and resultant ecological nonsustainability. Localized environmental degradation that has long accompanied population growth, industrialization, and rising consumerism has now acquired a global and often systemic dimension (e.g., climate change, disrupted nitrogen cycling, biodiversity loss). Thus, the economic intensification and technological advances that previously contributed to health gains have now expanded such that humanity's environmental (and ecological) footprint jeopardizes global population health. International data show, in general, a positive correlation of a population's health with level of affluence and size of per-person footprint. Yet, beyond a modest threshold, larger footprints afford negligible health gain and may impair health (e.g., via the rise of obesity). Furthermore, some lower-income countries have attained high levels of health. Many changes now needed to promote ecological (and social) sustainability will benefit local health. Continued improvement of global health could thus coexist with an equitably shared global environmental footprint.

Climate change, noncommunicable diseases, and development: the relationships and common policy opportunities.

The rapid growth in noncommunicable diseases (NCDs), including injury and poor mental health, in low- and middle-income countries and the widening social gradients in NCDs within most countries worldwide pose major challenges to health and social systems and to development more generally. As Earth's surface temperature rises, a consequence of human-induced climate change, incidences of severe heat waves, droughts, storms, and floods will increase and become more severe. These changes will bring heightened risks to human survival and will likely exacerbate the incidence of some NCDs, including cardiovascular disease, some cancers, respiratory health, mental disorders, injuries, and malnutrition. These two great and urgent contemporary human challenges-to improve global health, especially the control of NCDs, and to protect people from the effects of climate change-would benefit from alignment of their policy agendas, offering synergistic opportunities to improve population and planetary health. Well-designed climate change policy can reduce the incidence of major NCDs in local populations.

Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS.

The precise role played by HIV-specific cytotoxic T lymphocytes (CTL) in HIV infection remains controversial. Despite strong CTL responses being generated during the asymptomatic phase, the virus persists and AIDS ultimately develops. It has been argued that the virus is so variable, and the virus turnover so great that escape from CTL recognition would occur continually, but so far there is limited evidence for CTL escape. The opposing argument is that evidence for CTL escape is present but hard to find because multiple anti-HIV immune responses are acting simultaneously during the asymptomatic phase of infection. We describe six donors who make a strong CTL response to an immunodominant HLA-B27-restricted epitope. In the two donors who progressed to AIDS, CTL escape to fixation by the same mutation was observed, but only after 9-12 years of epitope stability. CTL escape may play an important role in the pathogenesis of HIV infection.

Large clonal expansions of CD8+ T cells in acute infectious mononucleosis.

Primary infection with Epstein-Barr virus often results in the clinical syndrome of acute infectious mononucleosis (glandular fever). This illness is characterized by a striking lymphocytosis, the nature of which has been controversial. We show that large monoclonal or oligoclonal populations of CD8+ T cells account for a significant proportion of the lymphocytosis and provide molecular evidence that these populations have been driven by antigen. The results suggest that the selective and massive expansion of a few dominant clones of CD8+ T cells is an important feature of the primary response to this virus.

HLA restriction of human cytotoxic T lymphocytes specific for influenza virus. Poor recognition of virus associated with HLA A2.

Cytotoxic T lymphocytes (CTL), specific for influenza A/X31 virus, were generated from human peripheral blood lymphocytes. These CTL lysed target cells that were infected with the same virus and that shared HLA A or B locus antigens. Minimal lysis was observed when HLA-D antigens were shared. Not all HLA A and B antigens were equally effective. Efficient lysis of target cells was seen when HLA A1, A3, B7, B8, B27 and BW21 were shared with the CTL, but when HLA A2 was the only shared antigen lysis was usually minimal. This deficiency in CTL function associated with HLA A2 was not absolute. It is suggested that the function of this antigen might be influenced by other surface molecules on the cell and in particular the other HLA products.