The ultrafast photoinduced ring-opening of 1,3-cyclohexadiene constitutes a textbook example of electrocyclic reactions in organic chemistry and a model for photobiological reactions in vitamin D ...synthesis. Although the relaxation from the photoexcited electronic state during the ring-opening has been investigated in numerous studies, the accompanying changes in atomic distance have not been resolved. Here we present a direct and unambiguous observation of the ring-opening reaction path on the femtosecond timescale and subångström length scale using megaelectronvolt ultrafast electron diffraction. We followed the carbon-carbon bond dissociation and the structural opening of the 1,3-cyclohexadiene ring by the direct measurement of time-dependent changes in the distribution of interatomic distances. We observed a substantial acceleration of the ring-opening motion after internal conversion to the ground state due to a steepening of the electronic potential gradient towards the product minima. The ring-opening motion transforms into rotation of the terminal ethylene groups in the photoproduct 1,3,5-hexatriene on the subpicosecond timescale.
Electrocyclic reactions are characterized by the concerted formation and cleavage of both σ and π bonds through a cyclic structure. This structure is known as a pericyclic transition state for ...thermal reactions and a pericyclic minimum in the excited state for photochemical reactions. However, the structure of the pericyclic geometry has yet to be observed experimentally. We use a combination of ultrafast electron diffraction and excited state wavepacket simulations to image structural dynamics through the pericyclic minimum of a photochemical electrocyclic ring-opening reaction in the molecule α-terpinene. The structural motion into the pericyclic minimum is dominated by rehybridization of two carbon atoms, which is required for the transformation from two to three conjugated π bonds. The σ bond dissociation largely happens after internal conversion from the pericyclic minimum to the electronic ground state. These findings may be transferrable to electrocyclic reactions in general.
Summary
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.
What is already known about this topic?
Atopic dermatitis (AD) is a chronic heterogeneous inflammatory skin disease with few approved therapies for patients with moderate‐to‐severe disease.
What does this study add?
These two phase III trials show that baricitinib, an oral inhibitor of Janus kinase 1 and 2, significantly improved clinical signs and symptoms of AD compared with placebo within the first 16 weeks of treatment.
Baricitinib may represent a first‐in‐class oral treatment option for adult patients with moderate‐to‐severe AD.
Linked Comment: Drucker. Br J Dermatol 2020; 183:199–200.
Plain language summary available online
Summary
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.
Linked Comment: Blome. Br J Dermatol 2020; 183:609.
Plain language summary available online
The development of ultrafast gas electron diffraction with nonrelativistic electrons has enabled the determination of molecular structures with atomic spatial resolution. It has, however, been ...challenging to break the picosecond temporal resolution barrier and achieve the goal that has long been envisioned—making space- and-time resolved molecular movies of chemical reaction in the gas-phase. Recently, an ultrafast electron diffraction (UED) apparatus using mega-electron-volt (MeV) electrons was developed at the SLAC National Accelerator Laboratory for imaging ultrafast structural dynamics of molecules in the gas phase. The SLAC gas-phase MeV UED has achieved 65 fs root mean square temporal resolution, 0.63 Å spatial resolution, and 0.22 Å−1 reciprocal-space resolution. Such high spatial-temporal resolution has enabled the capturing of real-time molecular movies of fundamental photochemical mechanisms, such as chemical bond breaking, ring opening, and a nuclear wave packet crossing a conical intersection. In this paper, the design that enables the high spatial-temporal resolution of the SLAC gas phase MeV UED is presented. The compact design of the differential pump section of the SLAC gas phase MeV UED realized five orders-of-magnitude vacuum isolation between the electron source and gas sample chamber. The spatial resolution, temporal resolution, and long-term stability of the apparatus are systematically characterized.
The radiolysis of water is ubiquitous in nature and plays a critical role in numerous biochemical and technological applications. Although the elementary reaction pathways for ionized water have been ...studied, the short-lived intermediate complex and structural dynamic response after the proton transfer reaction remain poorly understood. Using a liquid-phase ultrafast electron diffraction technique to measure the intermolecular oxygen···oxygen and oxygen···hydrogen bonds, we captured the short-lived radical-cation complex OH(H
O
) that was formed within 140 femtoseconds through a direct oxygen···oxygen bond contraction and proton transfer, followed by the radical-cation pair dissociation and the subsequent structural relaxation of water within 250 femtoseconds. These measurements provide direct evidence of capturing this metastable radical-cation complex before separation, thereby improving our fundamental understanding of elementary reaction dynamics in ionized liquid water.
The conversion of light into usable chemical and mechanical energy is pivotal to several biological and chemical processes, many of which occur in solution. To understand the structure–function ...relationships mediating these processes, a technique with high spatial and temporal resolutions is required. Here, we report on the design and commissioning of a liquid-phase mega-electron-volt (MeV) ultrafast electron diffraction instrument for the study of structural dynamics in solution. Limitations posed by the shallow penetration depth of electrons and the resulting information loss due to multiple scattering and the technical challenge of delivering liquids to vacuum were overcome through the use of MeV electrons and a gas-accelerated thin liquid sheet jet. To demonstrate the capabilities of this instrument, the structure of water and its network were resolved up to the
3
rd hydration shell with a spatial resolution of 0.6 Å; preliminary time-resolved experiments demonstrated a temporal resolution of 200 fs.
Itch, skin pain, and sleep disturbance are burdensome symptoms in atopic dermatitis (AD) that negatively influence a patient's quality of life (QoL).
To evaluate the impact of baricitinib on ...patient-reported outcomes (PROs) in adult patients with moderate-to-severe AD, and explore the association between improvement in key signs and symptoms of AD with improvements in QoL and patient's assessment of disease severity.
Data were analyzed from two phase III monotherapy trials (BREEZE-AD1/BREEZE-AD2) in which patients were randomized 2:1:1:1 to once-daily placebo, baricitinib 1-mg, 2-mg, or 4-mg for 16 weeks and assessed using PRO measures.
At week 16, baricitinib 4-mg and 2-mg significantly reduced itch severity (Itch Numeric Rating Scale (NRS) (BREEZE-AD1: percent change from baseline −36.6% and −29.4% vs. placebo (-12.0%), p≤.001 and p≤.05; BREEZE-AD2: −47.2% and −46.9% vs. placebo (-16.6%), p≤.001). Baricitinib significantly reduced SCORing AD (SCORAD) pruritus (4-mg in BREEZE-AD1 and 2-mg in BREEZE-AD2) and Patient Oriented Eczema Measure (POEM) itch (both doses). Improvements in skin pain severity and sleep disturbance were also observed. Improvements in AD symptoms showed higher correlations with patients' assessment of AD severity and QoL than improvements in skin inflammation.
Baricitinib significantly improved symptoms in patients with moderate-to-severe AD.
NCT03334396 (BREEZE-AD1) and NCT03334422 (BREEZE-AD2).
Summary
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.
What is already known about this topic?
Assessing patient‐reported outcomes is critical in patient‐focused drug development.
The patient perspective on their own signs, symptoms and unmet needs provides a key clinical trial data source for evaluating treatment outcomes.
Clinically meaningful and content‐valid patient‐reported outcome (PRO) measures are required to collect these data in alopecia areata (AA) clinical trials.
What does this study add?
This study developed a content‐valid PRO measure for patients with AA to self‐report the status of their scalp hair loss.
This novel PRO measure allows scalp hair loss to be characterized into clinically meaningful gradations across the range of 0–100% missing scalp hair.
What are the clinical implications of this work?
The Scalp Hair Assessment PRO™ provides a new clinical outcome assessment of AA scalp hair loss for use in both clinical trials to evaluate the efficacy of novel treatments and in clinical practice to obtain a patient‐centred perspective on the key sign and symptom of AA.
With corresponding response options to the newly developed Alopecia Areata Investigator Global Assessment (AA‐IGA™), clinician and patient assessments are comparable to elucidate any perceived differences between respondents.
Linked Comment: Rencz. Br J Dermatol 2020; 183:986–987.
PDF
