Photobiomodulation in the infrared spectrum reverses the expansion of circulating natural killer cells and brain microglial activation in Sanfilippo mice.

Sanfilippo syndrome results from inherited mutations in genes encoding lysosomal enzymes that catabolise heparan sulfate (HS), leading to early childhood-onset neurodegeneration. This study explores the therapeutic potential of photobiomodulation (PBM), which is neuroprotective and anti-inflammatory in several neurodegenerative diseases; it is also safe and PBM devices are readily available. We investigated the effects of 10-14 days transcranial PBM at 670 nm (2 or 4 J/cm2/day) or 904 nm (4 J/cm2/day) in young (3 weeks) and older (15 weeks) Sanfilippo or mucopolysaccharidosis type IIIA (MPS IIIA) mice. Although we found no PBM-induced changes in HS accumulation, astrocyte activation, CD206 (an anti-inflammatory marker) and BDNF expression in the brains of Sanfilippo mice, there was a near-normalisation of microglial activation in older MPS IIIA mice by 904 nm PBM, with decreased IBA1 expression and a return of their morphology towards a resting state. Immune cell immunophenotyping of peripheral blood with mass cytometry revealed increased pro-inflammatory signalling through pSTAT1 and p-p38 in NK and T cells in young but not older MPS IIIA mice (5 weeks of age), and expansion of NK, B and CD8+ T cells in older affected mice (17 weeks of age), highlighting the importance of innate and adaptive lymphocytes in Sanfilippo syndrome. Notably, 670 and 904 nm PBM both reversed the Sanfilippo-induced increase in pSTAT1 and p-p38 expression in multiple leukocyte populations in young mice, while 904 nm reversed the increase in NK cells in older mice. In conclusion, this is the first study to demonstrate the beneficial effects of PBM in Sanfilippo mice. The distinct reduction in microglial activation and NK cell pro-inflammatory signalling and number suggests PBM may alleviate neuroinflammation and lymphocyte activation, encouraging further investigation of PBM as a standalone, or complementary therapy in Sanfilippo syndrome.

Interactions between the aging brain and motor task complexity across the lifespan: balancing brain activity resource demand and supply.

The Compensation Related Utilization of Neural Circuits Hypothesis (CRUNCH) proposes a framework for understanding task-related brain activity changes as a function of healthy aging and task complexity. Specifically, it affords the following predictions: (i) all adult age groups display more brain activation with increases in task complexity, (ii) older adults show more brain activation compared with younger adults at low task complexity levels, and (iii) disproportionately increase brain activation with increased task complexity, but (iv) show smaller (or no) increases in brain activation at the highest complexity levels. To test these hypotheses, performance on a bimanual tracking task at 4 complexity levels and associated brain activation were assessed in 3 age groups (20-40, 40-60, and 60-80 years, n = 99). All age groups showed decreased tracking accuracy and increased brain activation with increased task complexity, with larger performance decrements and activation increases in the older age groups. Older adults exhibited increased brain activation at a lower complexity level, but not the predicted failure to further increase brain activity at the highest complexity level. We conclude that older adults show more brain activation than younger adults and preserve the capacity to deploy increased neural resources as a function of task demand.

Long-term efficacy and safety of baricitinib in patients with severe alopecia areata: 104-week results from BRAVE-AA1 and BRAVE-AA2.

BACKGROUND: Efficacy of the Janus kinase (JAK) inhibitor baricitinib for severe alopecia areata (AA) continuously increased over 52 weeks in two Phase 3 trials. There are limited long-term data on JAK inhibitors in AA. OBJECTIVES: To evaluate efficacy and safety of baricitinib for severe AA through 104 weeks of continuous therapy. METHODS: Integrated data from the BRAVE-AA1 and BRAVE-AA2 Phase 3 trials included adults with Severity of Alopecia Tool (SALT) scores ≥50 (≥50% scalp hair loss) randomized to and continuously treated with 2-mg or 4-mg baricitinib through Week 104. Patients who qualified to remain on continuous treatment included subjects who achieved SALT score ≤20 at Week 52 (Week-52 responders; 2-mg: N = 65; 4-mg: N = 129) and baricitinib 4-mg-treated patients who had SALT score >20 at Week 52 but achieved SALT score ≤20 at prior visit(s) and/or had significant improvement in eyebrow or eyelash hair growth relative to baseline by Week 52 (Week-52 mixed responders; N = 110). Week-104 outcomes included the proportion of patients achieving SALT score ≤20 (≤20% scalp hair loss). Data were censored after treatment discontinuation. RESULTS: Among baricitinib 4-mg-treated and baricitinib 2-mg-treated Week-52 responders, 90.7% and 89.2%, respectively, maintained SALT score ≤20 at Week 104. Among Week-52 mixed responders, 39.1% reached SALT score ≤20 by Week 104. Continued improvement in eyebrow and eyelash regrowth was observed across groups. The most frequent treatment-emergent adverse events were COVID-19, upper respiratory tract infection, headache, nasopharyngitis, acne, urinary tract infection and creatine phosphokinase increase. CONCLUSIONS: Baricitinib demonstrated a high level of maintenance of efficacy over 104 weeks in patients with severe AA. Efficacy increased in Week-52 mixed responders, illustrating that long-term treatment is necessary to observe maximum benefit in some patients. No new safety signals were observed.

medna-metadata: an open-source data management system for tracking environmental DNA samples and metadata.

MOTIVATION: Environmental DNA (eDNA), as a rapidly expanding research field, stands to benefit from shared resources including sampling protocols, study designs, discovered sequences, and taxonomic assignments to sequences. High-quality community shareable eDNA resources rely heavily on comprehensive metadata documentation that captures the complex workflows covering field sampling, molecular biology lab work, and bioinformatic analyses. There are limited sources that provide documentation of database development on comprehensive metadata for eDNA and these workflows and no open-source software. RESULTS: We present medna-metadata, an open-source, modular system that aligns with Findable, Accessible, Interoperable, and Reusable guiding principles that support scholarly data reuse and the database and application development of a standardized metadata collection structure that encapsulates critical aspects of field data collection, wet lab processing, and bioinformatic analysis. Medna-metadata is showcased with metabarcoding data from the Gulf of Maine (Polinski et al., 2019). AVAILABILITY AND IMPLEMENTATION: The source code of the medna-metadata web application is hosted on GitHub (https://github.com/Maine-eDNA/medna-metadata). Medna-metadata is a docker-compose installable package. Documentation can be found at https://medna-metadata.readthedocs.io/en/latest/?badge=latest. The application is implemented in Python, PostgreSQL and PostGIS, RabbitMQ, and NGINX, with all major browsers supported. A demo can be found at https://demo.metadata.maine-edna.org/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Gustation in insects: taste qualities and types of evidence used to show taste function of specific body parts.

The insect equivalent of taste buds are gustatory sensilla, which have been found on mouthparts, pharynxes, antennae, legs, wings, and ovipositors. Most gustatory sensilla are uniporous, but not all apparently uniporous sensilla are gustatory. Among sensilla containing more than one neuron, a tubular body on one dendrite is also indicative of a taste sensillum, with the tubular body adding tactile function. But not all taste sensilla are also tactile. Additional morphological criteria are often used to recognize if a sensillum is gustatory. Further confirmation of such criteria by electrophysiological or behavioral evidence is needed. The five canonical taste qualities to which insects respond are sweet, bitter, sour, salty, and umami. But not all tastants that insects respond to easily fit in these taste qualities. Categories of insect tastants can be based not only on human taste perception, but also on whether the response is deterrent or appetitive and on chemical structure. Other compounds that at least some insects taste include, but are not limited to: water, fatty acids, metals, carbonation, RNA, ATP, pungent tastes as in horseradish, bacterial lipopolysaccharides, and contact pheromones. We propose that, for insects, taste be defined not only as a response to nonvolatiles but also be restricted to responses that are, or are thought to be, mediated by a sensillum. This restriction is useful because some of the receptor proteins in gustatory sensilla are also found elsewhere.

Forecasting emergent risks in advanced AI systems: an analysis of a future road transport management system.

Artificial Intelligence (AI) is being increasingly implemented within road transport systems worldwide. Next generation of AI, Artificial General Intelligence (AGI) is imminent, and is anticipated to be more powerful than current AI. AGI systems will have a broad range of abilities and be able to perform multiple cognitive tasks akin to humans that will likely produce many expected benefits, but also potential risks. This study applied the EAST Broken Links approach to forecast the functioning of an AGI system tasked with managing a road transport system and identify potential risks. In total, 363 risks were identified that could have adverse impacts on the stated goals of safety, efficiency, environmental sustainability, and economic performance of the road system. Further, risks beyond the stated goals were identified; removal from human control, mismanaging public relations, and self-preservation. A diverse set of systemic controls will be required when designing, implementing, and operating future advanced technologies.Practitioner summary: This study demonstrated the utility of HFE methods for formally considering risks associated with the design, implementation, and operation of future technologies. This study has implications for AGI research, design, and development to ensure safe and ethical AGI implementation.

Network-specific differences in transient brain activity at rest are associated with age-related reductions in motor performance.

Multiple functional changes occur in the brain with increasing age. Among those, older adults typically display more restricted fluctuations of brain activity, both during resting-state and task execution. These altered dynamic patterns have been linked to reduced task performance across multiple behavioral domains. Windowed functional connectivity, which is typically employed in the study of connectivity dynamics, however, might not be able to properly characterize moment-to-moment variations of individual networks. In the present study, we used innovation-driven co-activation patterns (ICAP) to overcome this limitation and investigate the length (duration) and frequency (innovation) in which various brain networks emerged across the adult lifespan (N= 92) during a resting-state period. We identified a link between increasing age and a tendency to engage brain areas with distinct functional associations simultaneously as a single network. The emergence of isolated and spatially well-defined visual, motor, frontoparietal, and posterior networks decreased with increased age. This reduction in dynamics of specialized networks mediated age-related performance decreases (i.e., increases in interlimb interference) in a bimanual motor task. Altogether, our findings demonstrated that older compared to younger adults tend to activate fewer network configurations, which include multiple functionally distinct brain areas. The reduction in independent emergence of functionally well-defined and task-relevant networks may reflect an expression of brain dedifferentiation and is likely associated with functional modulatory deficits, negatively impacting motor behavior.

Stress Modulates the Balance between Hippocampal and Motor Networks during Motor Memory Processing.

The functional interaction between hippocampo- and striato-cortical regions during motor sequence learning is essential to trigger optimal memory consolidation. Based on previous evidence from other memory domains that stress alters the balance between these systems, we investigated whether exposure to stress prior to motor learning modulates motor memory processes. Seventy-two healthy young individuals were exposed to a stressful or nonstressful control intervention prior to training on a motor sequence learning task in a magnetic resonance imaging (MRI) scanner. Consolidation was assessed with an MRI retest after a sleep episode. Behavioral results indicate that stress prior to learning did not influence motor performance. At the neural level, stress induced both a larger recruitment of sensorimotor regions and a greater disengagement of hippocampo-cortical networks during training. Brain-behavior regression analyses showed that while this stress-induced shift from (hippocampo-)fronto-parietal to motor networks was beneficial for initial performance, it was detrimental for consolidation. Our results provide the first experimental evidence that stress modulates the neural networks recruited during motor memory processing and therefore effectively unify concepts and mechanisms from diverse memory fields. Critically, our findings suggest that intersubject variability in brain responses to stress determines the impact of stress on motor learning and subsequent consolidation.

Investigating dilution ventilation control strategies in a modern U.S. school bus in the context of the COVID-19 pandemic.

Fresh air ventilation has been identified as a widely accepted engineering control effective at diluting air contaminants in enclosed environments. The goal of this study was to evaluate the effects of selected ventilation measures on air change rates in school buses. Air changes per hour (ACH) of outside air were measured using a well-established carbon dioxide (CO2) tracer gas decay method. Ventilation was assessed while stationary and while traversing standardized route during late autumn/winter months in Colorado. Seven CO2 sensors located at the driver's seat and at passenger seats in the front, middle, and rear of the bus yielded similar and consistent measurements. Buses exhibited little air exchange in the absence of ventilation (ACH = 0.13 when stationary; ACH = 1.85 when mobile). Operating the windshield defroster to introduce fresh outside air increased ACH by approximately 0.5-1 ACH during mobile and stationary phases. During the mobile phase (average speed of 23 miles per hour (mph)), the combination of the defroster and two open ceiling hatches (with a powered fan on the rear hatch) yielded an ACH of approximately 9.3 ACH. A mobile phase ACH of 12.4 was achieved by the combination of the defroster, ceiling hatches, and six passenger windows open 2 inches in the middle area of the bus. A maximum mobile phase ACH of 22.1 was observed by using the defroster, open ceiling hatches, driver window open 4 inches, and every other passenger window open 2 inches. For reference, ACHs recommended in patient care settings where patients are being treated for airborne infectious diseases range from 6 to ≥12 ACHs. The results indicate that practical ventilation protocols on school buses can achieve air change rates thought to be capable of reducing airborne viral transmission to the bus driver and student passengers during the COVID-19 pandemic.

Classical Resummation and Breakdown of Strong-Field QED.

QED perturbation theory has been conjectured to break down in sufficiently strong backgrounds, obstructing the analysis of strong-field physics. We show that the breakdown occurs even in classical electrodynamics, at lower field strengths than previously considered, and that it may be cured by resummation. As a consequence, an analogous resummation is required in QED. A detailed investigation shows, for a range of observables, that unitarity removes diagrams previously believed to be responsible for the breakdown of QED perturbation theory.

Increased paediatric presentations of severe diabetic ketoacidosis in an Australian tertiary centre during the COVID-19 pandemic.

AIMS: To determine if the frequency of severe diabetic ketoacidosis at presentation of new-onset type 1 diabetes to an Australian tertiary centre increased during the initial period of restrictions resulting from the COVID-19 pandemic (March to May 2020). METHODS: Data were collected on presentations of newly diagnosed type 1 diabetes as well as on all paediatric presentations to the emergency department of a tertiary centre between 2015 and 2020. Data from the period of initial COVID restrictions in Australia (March to May 2020) were compared to the period March to May of the previous 5 years (pre-pandemic periods). RESULTS: The number of new diagnoses of type 1 diabetes was comparable in the pandemic period and pre-pandemic periods (11 in 2020 vs range 6-10 in 2015-2019). The frequency of severe diabetic ketoacidosis was significantly higher in the pandemic period compared to the pre-pandemic periods (45% vs 5%; P <0.003), odds ratio 16.7 (95% CI 2.0, 194.7). The overall frequency of diabetic ketoacidosis was also significantly higher during the pandemic period (73% vs 26%; P <0.007), odds ratio 7.5 (95% CI 1.7, 33.5). None of the individuals tested positive for COVID-19. Presentations of people aged <18 years to the emergency department decreased by 27% in the pandemic period compared to the average of the pre-pandemic periods (4799 vs 6550; range 6268 to 7131). CONCLUSIONS: A significant increase in the frequency of severe diabetic ketoacidosis at presentation of type 1 diabetes was observed during the initial period of COVID-19 restrictions. We hypothesize that concern about presenting to hospital during a pandemic led to a delay in diagnosis. These data have important implications for advocacy of seeking healthcare for non-pandemic-related conditions during a global pandemic.

Economic analysis of prenatal fetoscopic vs open-hysterotomy repair of open neural tube defect.

OBJECTIVE: Fetal repair of an open neural tube defect (ONTD) by open hysterotomy has been shown to reduce the need for ventriculoperitoneal shunting and improve motor outcomes for infants, but increases the risk of Cesarean section and prematurity. Fetoscopic repair is an alternative approach that may confer similar neurological benefits but allows for vaginal delivery and reduces the incidence of hysterotomy-related complications. We sought to compare the costs of care from fetal surgery until neonatal discharge, as well as the clinical outcomes, associated with each surgical approach. METHODS: This was a retrospective cohort study of patients who underwent prenatal ONTD repair, using either the open-hysterotomy or the fetoscopic approach, at a single institution between 2012 and 2018. Clinical outcomes were collected by chart review. A cost-consequence analysis was conducted from the hospital perspective, and included all inpatient and ambulatory hospital and physician costs incurred for the care of mothers and their infants, from the time of maternal admission for fetal ONTD repair up to postnatal maternal and infant discharge. Costs were estimated using cost-to-charge ratios for hospital billing and the Medicare physician fee schedule for physician billing. RESULTS: Seventy-eight patients were included in the analysis, of whom 47 underwent fetoscopic repair and 31 underwent open-hysterotomy repair. In the fetoscopic-repair group, compared with the open-repair group, fewer women underwent Cesarean section (53% vs 100%; P < 0.001) and the median gestational age at birth was significantly higher (38.1 weeks (interquartile range (IQR), 35.2-39.1 weeks) vs 35.7 weeks (IQR, 33.9-37.0 weeks); P < 0.001). No case of uterine dehiscence was observed in the fetoscopic-repair group, compared with an incidence of 16% in the open-repair group. After adjusting for baseline characteristics, there was no significant difference in the total cost of care between the fetoscopic-repair and the open-repair groups (median, $76 978 (IQR, $60 312-$115 386) vs $65 103 (IQR, $57 758-$108 103); P = 0.458). CONCLUSIONS: Fetoscopic repair of ONTD, when compared with the open-hysterotomy approach, reduces the incidence of Cesarean section and preterm delivery with no significant difference in total costs of care from surgery to infant discharge. This novel approach may represent a cost-effective alternative to improve maternal and neonatal outcomes for this high-risk population. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

High-Statistics Measurement of Neutrino Quasielasticlike Scattering at 6 GeV on a Hydrocarbon Target.

We measure neutrino charged-current quasielasticlike scattering on hydrocarbon at high statistics using the wideband Neutrinos at the Main Injector beam with neutrino energy peaked at 6 GeV. The double-differential cross section is reported in terms of muon longitudinal (p_{∥}) and transverse (p_{⊥}) momentum. Cross section contours versus lepton momentum components are approximately described by a conventional generator-based simulation, however, discrepancies are observed for transverse momenta above 0.5 GeV/c for longitudinal momentum ranges 3-5 and 9-20 GeV/c. The single differential cross section versus momentum transfer squared (dσ/dQ_{QE}^{2}) is measured over a four-decade range of Q^{2} that extends to 10 GeV^{2}. The cross section turnover and falloff in the Q^{2} range 0.3-10 GeV^{2} is not fully reproduced by generator predictions that rely on dipole form factors. Our measurement probes the axial-vector content of the hadronic current and complements the electromagnetic form factor data obtained using electron-nucleon elastic scattering. These results help oscillation experiments because they probe the importance of various correlations and final-state interaction effects within the nucleus, which have different effects on the visible energy in detectors.

High-protein meals require 30% additional insulin to prevent delayed postprandial hyperglycaemia.

AIM: To determine the amount of additional insulin required for a high-protein meal to prevent postprandial hyperglycaemia in individuals with type 1 diabetes using insulin pump therapy. METHODS: In this randomized cross-over study, 26 participants aged 8-40 years, HbA1c < 65 mmol/mol (8.1%), received a 50 g protein, 30 g carbohydrate, low-fat (< 1 g) breakfast drink over five consecutive days at home. A standard insulin dose (100%) was compared with additional doses of 115, 130, 145 and 160% for the protein, in randomized order. Doses were commenced 15-min pre-drink and delivered over 3 h using a combination bolus with 65% of the standard dose given up front. Postprandial glycaemia was assessed by 4 h of continuous glucose monitoring. RESULTS: The 100% dosing resulted in postprandial hyperglycaemia. From 120 min, ≥ 130% doses resulted in significantly lower postprandial glycaemic excursions compared with 100% (P < 0.05). A 130% dose produced a mean (sd) glycaemic excursion that was 4.69 (2.42) mmol/l lower than control, returning to baseline by 4 h (P < 0.001). From 120 min, there was a significant increase in the risk of hypoglycaemia compared with control for 145% [odds ratio (OR) 25.4, 95% confidence interval (CI) 5.5-206; P < 0.001) and 160% (OR 103, 95% CI 19.2-993; P < 0.001). Some 81% (n = 21) of participants experienced hypoglycaemia following a 160% dose, whereas 58% (n = 15) experienced hypoglycaemia following a 145% dose. There were no hypoglycaemic events reported with 130%. CONCLUSIONS: The addition of 30% more insulin to a standard dose for a high-protein meal, delivered using a combination bolus, improves postprandial glycaemia without increasing the risk of hypoglycaemia.

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.

Age-related differences in network flexibility and segregation at rest and during motor performance.

Brain networks undergo widespread changes in older age. A large body of knowledge gathered about those changes evidenced an increase of functional connectivity between brain networks. Previous work focused mainly on cortical networks during the resting state. Subcortical structures, however, are of critical importance during the performance of motor tasks. In this study, we investigated age-related changes in cortical, striatal and cerebellar functional connectivity at rest and its modulation by motor task execution. To that end, functional MRI from twenty-five young (mean age 21.5 years) and eighteen older adults (mean age 68.6 years) were analysed during rest and while performing a bimanual tracking task practiced over a two-week period. We found that inter-network connectivity among cortical structures was more positive in older adults both during rest and task performance. Functional connectivity within striatal structures decreased with age during rest and task execution. Network flexibility, the changes in network composition from rest to task, was also reduced in older adults, but only in networks with an age-related increase in connectivity. Finally, flexibility of areas in the prefrontal cortex were associated with lower error scores during task execution, especially in older adults. In conclusion, our findings indicate an age-related reduction in the ability to suppress irrelevant network communication, leading to less segregated and less flexible cortical networks. At the same time, striatal connectivity is impaired in older adults, while cerebellar connectivity shows heterogeneous age-related effects during rest and task execution. Future research is needed to clarify how cortical and subcortical connectivity changes relate to one another.

The ups and downs of low-carbohydrate diets in the management of Type 1 diabetes: a review of clinical outcomes.

Dietary management has been a mainstay of care in Type 1 diabetes since before the discovery of insulin when severe carbohydrate restriction was advocated. The use of insulin facilitated re-introduction of carbohydrate into the diet. Current management guidelines focus on a healthy and varied diet with consideration of glycaemic load, protein and fat. As a result of frustration with glycaemic outcomes, low-carbohydrate diets have seen a resurgence in popularity. To date, low-carbohydrate diets have not been well studied in the management of Type 1 diabetes. Studies looking at glycaemic outcomes from low-carbohydrate diets have largely been cross-sectional, without validated dietary data and with a lack of control groups. The participants have been highly motivated self-selected individuals who follow intensive insulin management practices, including frequent blood glucose monitoring and additional insulin corrections with tight glycaemic targets. These confounders limit the ability to determine the extent of the impact of dietary carbohydrate restriction on glycaemic outcomes. Carbohydrate-containing foods including grains, fruit and milk are important sources of nutrients. Hence, low-carbohydrate diets require attention to vitamin and energy intake to avoid micronutrient deficiencies and growth issues. Adherence to restricted diets is challenging and can have an impact on social normalcy. In individuals with Type 1 diabetes, adverse health risks such as diabetic ketoacidosis, hypoglycaemia, dyslipidaemia and glycogen depletion remain clinical concerns. In the present paper, we review studies published to date and provide clinical recommendations for ongoing monitoring and support for individuals who choose to adopt a low-carbohydrate diet. Strategies to optimize postprandial glycaemia without carbohydrate restriction are presented.

Impact of dietary protein on postprandial glycaemic control and insulin requirements in Type 1 diabetes: a systematic review.

AIM: Postprandial hyperglycaemia is a challenge for people living with Type 1 diabetes. In addition to carbohydrate, dietary protein has been shown to contribute to postprandial glycaemic excursions with recommendations to consider protein when calculating mealtime insulin doses. The aim of this review is to identify and synthesize evidence about the glycaemic impact of dietary protein and insulin requirements for individuals with Type 1 diabetes. METHODS: A systematic literature search of relevant biomedical databases was performed to identify research on the glycaemic impact of dietary protein when consumed alone, and in combination with other macronutrients in individuals with Type 1 diabetes. RESULTS: The review included 14 published studies dated from 1992 to 2018, and included studies that researched the impact of protein alone (n = 2) and protein in a mixed meal (n = 12). When protein was consumed alone a glycaemic effect was not seen until ≥ 75 g. In a carbohydrate-containing meal ≥ 12.5 g of protein impacted the postprandial glucose. Inclusion of fat in a high-protein meal enhanced the glycaemic response and further increased insulin requirements. The timing of the glycaemic effect from dietary protein ranged from 90 to 240 min. Studies indicate that the postprandial glycaemic response and insulin requirements for protein are different when protein is consumed alone or with carbohydrate and/or fat. CONCLUSIONS: This systematic review provides evidence that dietary protein contributes to postprandial glycaemic excursions and insulin requirements. These insights have important implications for the education of people with Type 1 diabetes and highlights the need for more effective insulin dosing strategies for mixed macronutrient meals.