The Alopecia Areata Investigator Global Assessment scale: a measure for evaluating clinically meaningful success in clinical trials.

BACKGROUND: Content-valid and clinically meaningful instruments are required to evaluate outcomes of therapeutic interventions in alopecia areata (AA). OBJECTIVES: To develop an Investigator's Global Assessment (IGA) to interpret treatment response in AA treatment studies. METHODS: Qualitative interviews were conducted in the USA with expert dermatologists and with patients with AA who had experienced ≥ 50% scalp-hair loss. Thematic data analysis identified critical outcomes and evaluated the content validity of the new IGA. RESULTS: Expert clinicians (n = 10) judged AA treatment success by the amount of scalp-hair growth (median 80% scalp hair). Adult (n = 25) and adolescent (n = 5) patients participated. Scalp-hair loss was the most bothersome AA sign/symptom for most patients. Perceived treatment success - short of 100% scalp hair - was the presence of ~ 70-90% scalp hair (median 80%). Using additional clinician and patient insights, the Alopecia Areata Investigator Global Assessment (AA-IGA™) was developed. This clinician-reported outcome assessment is an ordinal, static measure comprising five severity categories of scalp-hair loss. Nearly all clinicians and patients in this study agreed that, for patients with ≥ 50% scalp-hair loss, successful treatment would be hair regrowth resulting in ≤ 20% scalp-hair loss. CONCLUSIONS: We recommend using the Severity of Alopecia Tool to assess the extent (0-100%) of scalp-hair loss. The AA-IGA is a robust ordinal measure providing distinct and clinically meaningful gradations of scalp-hair loss that reflects patients' and expert clinicians' perspectives and treatment expectations. What is already known about this topic? The Severity of Alopecia Tool is widely used to assess the extent of scalp-hair loss in patients with alopecia areata. Guidelines define treatment success as a 50% improvement in scalp hair, and clinical trials have used dynamic thresholds of 50% and 90%. However, there is no clinical consensus on these endpoints, and patient perspectives on treatment success are unknown. What does this study add? Through qualitative interviews with 10 expert dermatologists and 30 patients with alopecia areata who had experienced ≥ 50% scalp-hair loss, we developed the Alopecia Areata Investigator Global Assessment (AA-IGA™) to measure five clinically meaningful gradations of alopecia areata scalp-hair loss that reflects patients' and clinicians' perspectives and expectations of treatment success in alopecia areata treatment studies. What are the clinical implications of this work? The AA-IGA is a robust ordinal measure that can inform clinical evaluation of alopecia areata treatment outcomes. The AA-IGA can be used to determine clinically meaningful treatment success for alopecia areata, with success defined by patients and clinicians as reaching ≤ 20% scalp-hair loss. Linked Comment: Blome. Br J Dermatol 2020; 183:609.

Development of the Scalp Hair Assessment PRO™ measure for alopecia areata.

BACKGROUND: Valid patient-reported outcome (PRO) measures are required to evaluate alopecia areata (AA) treatments. OBJECTIVES: To develop a content-valid and clinically meaningful PRO measure to assess AA scalp hair loss with scores comparable with the five-response-level Alopecia Areata Investigator Global Assessment (AA-IGA™). METHODS: A draft PRO measure was developed based on input from 10 clinical experts in AA. The PRO measure was cognitively debriefed, modified and finalized through two rounds of qualitative semistructured interviews with patients with AA who had experienced ≥ 50% scalp hair loss. Data were thematically analysed. RESULTS: Adults (round 1: n = 25; round 2: n = 15) and adolescents aged 15-17 years (round 1: n = 5) in North America participated. All patients named scalp hair loss as a key AA sign or symptom. Patients demonstrated the ability to self-report their current amount of scalp hair using percentages. In round 1 not all patients interpreted the measurement concept consistently; therefore, the PRO was modified to clarify the measurement concept to improve usability. Following modifications, patients in round 2 responded without difficulty to the PRO measure. Patients confirmed that they could use the five-level response scale to rate their scalp hair loss: no missing hair, 0%; limited, 1-20%; moderate, 21-49%; large, 50-94%; nearly all or all, 95-100%. Almost all patients deemed hair regrowth resulting in ≤ 20% scalp hair loss a treatment success. CONCLUSIONS: The Scalp Hair Assessment PRO™ is a content-valid, clinically meaningful assessment of distinct gradations of scalp hair loss for evaluating AA treatment for patients with ≥ 50% hair loss at baseline.

Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials.

BACKGROUND: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced atopic dermatitis (AD) severity in a phase II study with concomitant topical corticosteroids. OBJECTIVES: To evaluate the efficacy and safety of baricitinib in patients with moderate-to-severe AD who had an inadequate response to topical therapies. METHODS: In two independent, multicentre, double-blind, phase III monotherapy trials, BREEZE-AD1 and BREEZE-AD2, adults with moderate-to-severe AD were randomized 2 : 1 : 1 : 1 to once-daily placebo, baricitinib 1 mg, 2 mg, or 4 mg for 16 weeks. RESULTS: At week 16, more patients achieved the primary end point of Validated Investigator's Global Assessment of AD (0, 1) on baricitinib 4 mg and 2 mg compared with placebo in BREEZE-AD1 [N = 624; baricitinib 4 mg 16·8% (P < 0·001), 2 mg 11·4% (P < 0·05), 1 mg 11·8% (P < 0·05), placebo 4·8%], and BREEZE-AD2 [N = 615; baricitinib 4 mg 13·8% (P = 0·001), 2 mg 10·6% (P < 0·05), 1 mg 8·8% (P = 0·085), placebo 4·5%]. Improvement in itch was achieved as early as week 1 for 4 mg and week 2 for 2 mg. Improvements in night-time awakenings, skin pain and quality-of-life measures were observed by week 1 for both 4 mg and 2 mg (P ≤ 0·05, all comparisons). The most common adverse events in patients treated with baricitinib were nasopharyngitis and headache. No cardiovascular events, venous thromboembolism, gastrointestinal perforation, significant haematological changes, or death were observed with any baricitinib dosage. CONCLUSIONS: Baricitinib improved clinical signs and symptoms in patients with moderate-to-severe AD within 16 weeks of treatment and induced rapid reduction of itch. The safety profile remained consistent with prior findings from baricitinib clinical development in AD, with no new safety concerns.

Effect of in vitro maturation of mouse oocytes on the health and lifespan of adult offspring.

BACKGROUND: In vitro maturation of oocytes can, in some circumstances, provide an alternative approach to gonadotrophin-induced maturation in clinical settings. However, the consequences of these protocols on the long-term health of offspring are unknown. Here, the long-term health status and lifespans of offspring produced by in vitro maturation of mouse oocytes was compared with that of oocytes induced to mature in vivo using gonadotrophin treatment. METHODS: Mouse oocytes were matured in vitro using both an established optimized system and in the absence of amino acids to produce a suboptimal condition for maturation. Oocytes induced to mature in vivo with gonadotrophins constituted the control group. All metaphase II oocytes were fertilized in vitro and transferred at the 2-cell stage to the oviducts of pseudo-pregnant foster mothers for development to term. Offspring were subjected to a wide variety of physiological and behavioral tests for the first year of life and natural lifespan determined. RESULTS: There was no difference among the groups in lifespan or in most of the physiological and behavioral analyses. However, the pulse rate and cardiac output were slightly, but significantly, reduced in the optimized in vitro matured group compared with the in vivo matured group (P = 0.0119 and P = 0.0197, respectively). Surprisingly, these decreases were largely abrogated in the in vitro group matured without amino acids. CONCLUSIONS: Evidence presented here using a mouse model suggests that the in vitro maturation of oocytes has minimal effects on the long-term health of offspring. However, a finding of slight reductions in pulse rate and cardiac output may focus future clinical attention.

Subpolar North Atlantic Overturning and Gyre-Scale Circulation in the Summers of 2014 and 2016.

The Atlantic Meridional Overturning Circulation (AMOC) is a key component of the global climate system through its transport of heat and freshwater. The subpolar North Atlantic (SPNA) is a region where the AMOC is actively developed and shaped though mixing and water mass transformation and where large amounts of heat are released to the atmosphere. Two hydrographic transbasin sections in the summers of 2014 and 2016 provide highly spatially resolved views of the SPNA velocity and property fields on a line from Canada to Greenland to Scotland. Estimates of the AMOC, isopycnal (gyre-scale) transport, and heat and freshwater transport are derived from the observations. The overturning circulation, the maximum in northward transport integrated from the surface to seafloor and computed in density space, has a high range, with 20.6 ± 4.7 Sv in June-July 2014 and 10.6 ± 4.3 Sv in May-August 2016. In contrast, the isopycnal (gyre-scale) circulation was lowest in summer 2014: 41.3 ± 8.2 Sv compared to 58.6 ± 7.4 Sv in 2016. The heat transport (0.39 ± 0.08 PW in summer 2014, positive is northward) was highest for the section with the highest AMOC, and the freshwater transport was largest in summer 2016 when the isopycnal circulation was high (-0.25 ± 0.08 Sv). Up to 65% of the heat and freshwater transport was carried by the isopycnal circulation, with isopycnal property transport highest in the western Labrador Sea and the eastern basins (Iceland Basin to Scotland).

Antimicrobial peptides: mediators of innate immunity as templates for the development of novel anti-infective and immune therapeutics.

Antimicrobial molecules are ancient and essential small cationic molecules of the host defence system which are found in a wide variety of species. They display antimicrobial activity against a wide range of bacteria, fungi and viruses, an activity that has been mostly attributed to the disruption of microbial membranes. In this article, we will review the "classical" functions of 3 classes of antimicrobial molecules, namely defensins, cathelicidins, and the four-disulfide core proteins secretory leukocyte proteinase inhibitor (SLPI) and elafin. In addition to the study of their expression in a variety of cell types and the regulation of their production, we will also describe novel properties of these molecules that have been highlighted by recent studies. These include their ability to chemoattract a variety of inflammatory, immune and other cell types (neutrophils, macrophages, monocytes, lymphocytes, mast cells, epithelial cells) in vitro and in vivo. In addition, we will discuss the potential use of these newly discovered properties for therapeutic or vaccination purposes, using protein- or gene-transfer based methodologies. Finally, we will examine in an extensive fashion the strategies used by microorganisms to circumvent and subvert host defence mechanisms, such as the modifications of cell membranes and walls, the secretion of inactivating proteins and proteases and the down-regulation of expression of antimicrobial molecules. Increased understanding of the mechanisms used by both the host and the microbes to 'win the battle' may ultimately lead to new therapeutic strategies aimed to treat infectious diseases.

A comparison of 24-h average blood pressures and blood pressure load following exercise.

Although the use of 24-h ambulatory blood pressure monitoring has been recommended in the study of blood pressure and exercise, consistent results have not been found for average 24-h systolic or diastolic blood pressures. Systolic load and diastolic load (the percentage of pressures >140/90 mm Hg during daytime hours and >120/80 mm Hg during sleep) have recently been identified as an important variable, but has had limited use with exercise. The purpose of this study was to compare the average systolic and diastolic pressures to systolic and diastolic loads from 24-h data recorded after a 50-min treadmill walk at 50% VO2max to data from a nonexercise control day. Subjects were 36 normotensive (116.9 +/- 10.7/77.0 +/- 8.9 mm Hg) and 25 hypertensive (141.0 +/- 13.7/96.6 +/- 9.0 mm Hg) adults. No significant differences were found for systolic and diastolic pressures or loads between the control and exercise days for normotensives. Even though no significant changes were found for any of the average systolic and diastolic pressures between the control and exercise days for the hypertensives, significant reductions were found in systolic load for 24-h (-25.7%), day (6 AM to 10 PM, -23.1%), work (6 AM to 5 PM, -22.9%), and leisure (5 PM to 10 PM, -26.7%) periods; and in diastolic load for the work (-22.5%) period. Thus, the measurement of systolic and diastolic load may be more sensitive than average systolic and diastolic blood pressures for the detection of 24-h ambulatory blood pressure changes with exercise in borderline hypertension.

The magnitude and duration of ambulatory blood pressure reduction following acute exercise.

The purpose of this study was to observe the magnitude and duration of the ambulatory blood pressure (BP) reduction following exercise and to identify the peak intervals of BP reduction throughout the 24-h diurnal period. Subjects were 25 normo- (N = 116.7/ 78.2+/-10.0/7.2 mm Hg) and 21 hypertensive (H = 140.8/96.9+/-13.9/9.6 mm Hg) adults. Twenty-four hour ambulatory blood pressures (SBP = systolic and DBP = diastolic) were recorded following exercise (E = 50 min @ 50% VO2 max) and during a non-exercise control day (C). The 24-h pressures were compared between the E and C days for (1) duration and magnitude of the BP reduction following exercise, and for (2) the time of day for the diurnal patterns to exhibit reductions in BP. No BP differences were found for N between E and C days. Significant reductions in BP were found for 24-h average SBP (decrease 6.8 mm Hg) and DBP (decrease 4.1 mm Hg), daytime (06.00-22.00 hrs) SBP (decrease 6.9 mm Hg) and DBP (decrease 3.3 mm Hg), and sleep (22.00-06.00) SBP (decrease 5.1 mm Hg) and DBP (decrease 4.4 mm Hg) for H subjects only. H also demonstrated an 11 h reduction in SBP (chi = decrease 8.3+/-2.2 mm Hg) and 4h reduction in DBP (chi = decrease 6.0+/-1.7 mm Hg) following exercise. For the diurnal variation, the peak interval of reduction in SBP (chi = 17.0+/-2.6 mm Hg) was for 11 h; from 11.00-21.00 hrs. For DBP, a significant reduction (chi = decrease 5.7+/-0.7 mm Hg) was found for 5 h; from 11.00-15.00 h. Thus, exercise reduces both systolic and diastolic BP for a significant length of time postexercise as well as reduces pressures during the time of day that typically exhibits higher diurnal pressures.

Effect of exercise on milk immunoglobulin A.

The major immunoglobulin (Ig) in human secretions is IgA. The immune properties of breast milk are well documented; however, the immunological influence of maximal exercise has not been established. The objective of this study was to investigate the role that exercise has on breast milk IgA and IgA subclasses. Breast milk was collected from 17 lactating women (4.6 +/- 2.3 months postpartum) before and after randomized exercise and control periods. The exercise treatment was a maximal graded treadmill test (VO2max = 30.3 +/- 5.7 mL x min-1 x kg-1). Milk was collected at rest, the breasts were emptied, and samples obtained 10, 30, and 60 min following either exercise or 30-min control rest periods. IgA concentrations were established by enzyme-linked immunosorbent assay. The results indicated that samples taken 10 and 30 min after the exercise period had significantly lower (P < or = 0.05) milk IgA concentrations (21.0 +/- 1.8 and 21.8 +/- 1.4 microg x mL-1, respectively) than the corresponding control resting samples (52.8 +/- 3.5 and 79.3 +/- 7.7 microg x mL-1). The exercise samples were similar to the control samples at 60 min (134.0 +/- 24.6 and 116.0 +/- 15.4 microg x mL-1, respectively), indicating that by 1 h, milk IgA production had recovered. The IgA1 data showed a similar significant decrease (P < or = 0.05) at 10 min postexercise, which also returned to control concentrations by the 30- and 60-min collection intervals. There was no significant change in the milk IgA2 concentrations at any of the time points studied. Milk IgA concentrations increased significantly in both exercise and resting control groups after the breasts were emptied, suggesting that breast emptying stimulated milk IgA synthesis. The results provide evidence that exercise alters milk IgA and IgA1 concentrations for 10-30 min after exhaustive exercise, but recovers by 1 h, and provide additional support for exercise effects on the mucosal immune system.

Adverse skin and joint reactions associated with oral antibiotics in children: the role of cefaclor in serum sickness-like reactions.

OBJECTIVE: To review presentations to Princess Margaret Hospital Emergency Department (PMH ED) with adverse joint and skin reactions associated with the use of oral antibiotics, to describe the clinical course of children with cefaclor-related serum sickness-like reactions (cefaclor SSLR) and compare these with cases reported to the Adverse Drug Reactions Advisory Committee (ADRAC). METHODS: Twelve-month retrospective review of presentations to a tertiary paediatric ED (42,000 visits annually) via an ED computer database search and review of medical charts of children presenting with joint or skin reactions. Telephone interviews were conducted with the caregivers of children with cefaclor SSLR. RESULTS: Adverse skin or joint reactions occurred in 150 children; 70 after cefaclor alone, 10 after cefaclor in combination with other antibiotics and 70 after other antibiotic courses. SSLR occurred in 44 children; 32 after cefaclor alone, five after cefaclor in combination with other antibiotics and seven after other single antibiotics. In children with cefaclor SSLR, otitis media was the most common indication (59.4%), another 18.8% had viral illnesses. Prolonged sequelae occurred in four children, a situation not previously reported. Sixty reports of paediatric cefaclor SSLR were made to ADRAC during the study period, none originated from PMH ED. CONCLUSIONS: Cefaclor was associated with 53.3% of oral antibiotic related skin and joint adverse reactions and 84.1% of SSLR. The indications for its use in paediatric illness require careful reconsideration. ADRAC data under-represents the incidence of cefaclor SSLR.

Finger-movement tracking scores in healthy subjects.

The purpose of this study was to examine the effects of age, sex, and hand preference on precise control of voluntary movement at the index finger metacarpophalangeal joint in able-bodied volunteers. An electrogoniometer was attached to this joint and connected to a computer. The computer screen displayed a sine wave target that each subject attempted to track with careful extension and flexion finger movements. Accuracy index scores were calculated for the extension phases, flexion phases, and the total sine wave. Each subject performed three tracking trials and the average for each of the above scores was computed. The results showed that younger subjects tracked significantly more accurately than older subjects and men tracked significantly more accurately than women. Also, the subjects tracking with the nonpreferred hand (15 right, 105 left) tracked significantly more accurately than those subjects tracking with the preferred hand (112 right, 8 left) in the flexion phases of the test. The data from these able-bodied subjects provide a base for comparison of patients' data, which may be helpful in the early recognition and monitoring of problems with precision in movement control.

Inhibition of antimicrobial peptides by group A streptococci: SIC and DRS.

SIC (streptococcal inhibitor of complement) is a 31 kDa protein secreted by a few highly virulent strains of GAS (group A streptococci), predominantly by the M1 strain. Initially described as an inhibitor of the membrane attack complex of complement, it has turned out to be a polyfunctional inhibitor of the innate mucosal immune response. The SIC protein sequence contains three domains: an N-terminal SRR (short repeat region), followed by three longer tandem repeats [LRR (long repeat region)] and a C-terminal PRR (proline-rich region). SIC inhibits the antibacterial activity of a wide range of antimicrobial peptides and proteins: i.e. lysozyme, SLPI (secretory leucocyte proteinase inhibitor), LL-37, hNP-1 (human neutrophil peptide-1) and the human beta-defensins 1, 2 and 3. Analysis of the functional properties of recombinant domains of SIC shows that binding and inhibition of lysozyme and human beta-defensin-3 require the SRR+LRR, as does binding to SLPI. Complement inhibition is confined to the SRR. M12 GAS secrete a protein 'distantly related to SIC' (DRS). DRS contains a C-terminal PRR which is significantly similar to that of SIC, but it has no central LRR and the N-terminal SRR is very different. DRS inhibits human beta-defensin-3, but has no effect on lysozyme, SLPI or complement.

Nurses as end-user searchers of the literature on CD-ROM.

As the resource center for nursing information, the staff development department is the ideal location for facilitation of end-user searching of the nursing and medical literature. The authors report on a project undertaken to encourage searching of CD-ROM databases to improve patient care.

Pneumococcal meningitis: clinical course and resource use in Western Australian children.

OBJECTIVES: Paediatric pneumococcal meningitis causes high rates of neurological sequelae and is presenting challenges due to the emergence of antibiotic resistance. Diagnosis can be difficult and management is frequently complicated and resource intensive. This population-based study outlines the diagnosis, clinical course and initial resource use of Western Australian (WA) children diagnosed between 1990 and 2000. METHODS: The charts of all rural and metropolitan children discharged from all WA hospitals with International Classification of Disease 9 and 10 codes of pneumococcal or streptococcal meningitis from the Health Department's Hospital Morbidity Data System were reviewed retrospectively. RESULTS: Ninety-four episodes of pneumococcal meningitis were confirmed (median age 12.4 months). Initial diagnosis was often difficult with a suggestive prodrome in less than one quarter of cases and a median of two reviews until diagnosis (range 1-7). The median duration of hospitalization was 11.6 days, 41.5% were admitted to the Intensive Care Unit (ICU), and 47.9% had seizures. There were eight related deaths and neurological sequelae occurred in 24. Initial hospitalization cost on average $A 19,900. Penicillin resistance was first noted in 1993 and occurred in 4.6% of isolates. Most cases (84.5%) were caused by serotypes contained in the currently available seven-valent conjugate vaccine. CONCLUSIONS: Pneumococcal meningitis is often difficult to diagnose, necessitates long and frequently complicated in-patient stays and has high rates of neurological sequelae. It is possible to prevent most cases with new conjugate vaccines.

Pneumococcal meningitis in Western Australian children: epidemiology, microbiology and outcome.

OBJECTIVES: Pneumococcal meningitis is now vaccine-preventable but continues to cause high rates of neurological sequelae internationally. Population-based epidemiology, outcome and microbiology data are necessary to target vaccination strategies. This study outlines these key areas for Western Australian children diagnosed 1990-2000. METHODS: The charts of all rural and metropolitan children with International Classification of Disease 9 and 10 discharge codes of pneumococcal or streptococcal meningitis from the Health Department's Hospital Morbidity Data System were reviewed. RESULTS: Over 10.5 years, 94 episodes were confirmed. The average annual incidence for children under 2 years was 13.45 per 100 000 and 0.66 per 100 000 for children 2 years or older. Indigenous children had an almost seven-fold increased risk compared to non-Indigenous (with 78.55 per 100 000 in the under two-year Indigenous group). Eight children died and 24 of the survivors had neurological sequelae. Penicillin resistance occurred in four of 87 isolates. One quarter of the cohort qualify under the current Australian policy of vaccination of high-risk children with seven-valent conjugate (7vPCV) vaccine. Most isolates (49/58) were 7vPCV serotypes, however, Indigenous populations were less well-covered (58.3% covered vs 91.3% of isolates from non-Indigenous children). Indigenous coverage would be improved to 75% with 11-valent conjugate vaccine. CONCLUSIONS: Indigenous children and those under 2 years are most affected by pneumococcal meningitis and remain primary vaccination targets. Three quarters of these children would not be protected by a policy of vaccination of only high-risk children with 7vPCV--improved protection requires higher valencies for Indigenous populations and universal infant vaccination.