Optimizing maintenance therapy in responders to abrocitinib induction: A post hoc analysis of JADE REGIMEN.

BACKGROUND: Treatment optimization may require dosing flexibility. The Phase 3 JADE REGIMEN trial (NCT03627767) evaluated maintenance of abrocitinib 200 mg-induced response in patients with moderate-to-severe atopic dermatitis (AD) randomly assigned to subsequent maintenance with continuous-dose abrocitinib (200 mg), reduced-dose abrocitinib (100 mg) or placebo. Maintenance with continuous-dose abrocitinib was associated with a stronger prevention of disease flares, but also with a higher occurrence of adverse events, compared with the reduced dose. OBJECTIVE: This post hoc analysis of JADE REGIMEN aimed to identify predictors of not flaring during the maintenance period and to generate tools that can be used to assess probability of not flaring. METHODS: Data were analysed from patients who responded to abrocitinib 200 mg induction therapy (12 weeks) and were randomly assigned to receive abrocitinib (200 mg or 100 mg) or placebo in the 40-week maintenance period. Demographic and baseline disease characteristics and level of response to induction were evaluated for association with not flaring using logistic regression. Parameters with a significant (p < 0.15) interaction with the treatment arm were fitted into a multivariable regression model, which was used to assess probability of not flaring. RESULTS: Lower percentage body surface area affected at baseline (p = 0.09), absence of prior exposure to systemic agents (p = 0.02) and greater percentage change in EASI from baseline to randomization (p < 0.001) were identified as predictors of not flaring with abrocitinib. In both abrocitinib arms, percentage change in EASI from baseline to end of induction (Week 12) was the major contributor to the probability of not flaring in the maintenance period. CONCLUSIONS: Maintenance of response using reduced-dose abrocitinib 100 mg may be feasible for patients with lower baseline disease severity and strong response to abrocitinib 200 mg induction treatment.

Patient-reported outcomes from the JADE COMPARE randomized phase 3 study of abrocitinib in adults with moderate-to-severe atopic dermatitis.

BACKGROUND: In JADE COMPARE, abrocitinib improved severity of atopic dermatitis (AD) and demonstrated rapid itch relief. OBJECTIVES: We examined clinically meaningful improvements in selected patient-reported outcomes (PROs). METHODS: JADE COMPARE was a multicentre, phase 3 randomized, double-blind, placebo-controlled trial. Adults with moderate-to-severe AD were randomized 2:2:2:1 to receive 16 weeks of oral abrocitinib 200 or 100 mg once daily, dupilumab 300 mg subcutaneous injection every 2 weeks, or placebo, with background topical therapy. PROs included Dermatology Life Quality Index (DLQI), Patient-Oriented Eczema Measure (POEM), Night Time Itch Scale (NTIS), Pruritus and Symptoms Assessment for Atopic Dermatitis, Patient Global Assessment, SCORing Atopic Dermatitis, and Hospital Anxiety and Depression Scale. RESULTS: At week 16, the proportion of patients achieving POEM scores <3 was 21.3% and 11.7% for 200 and 100 mg abrocitinib, 12.4% for dupilumab, and 4.8% for placebo (vs. abrocitinib, P < 0.0001 and P = 0.04). Proportion achieving ≥4-point improvement from baseline in NTIS severity was 64.3% and 52.4% for 200 and 100 mg abrocitinib, 54.0% for dupilumab, and 34.4% for placebo (vs. abrocitinib, P < 0.0001 and P = 0.007). Proportion achieving ≥4-point improvement from baseline in DLQI was 85.0% and 74.4% for 200 and 100 mg abrocitinib, 83.4% for dupilumab, and 59.7% for placebo (vs. abrocitinib, P < 0.0001 and P = 0.005). CONCLUSION: Significant improvements in PROs were demonstrated with both abrocitinib doses vs. placebo, and abrocitinib 200 mg provided numerically greater effects compared with dupilumab in patients with moderate-to-severe AD.

Patient perspectives of atopic dermatitis: comparative analysis of terminology in social media and scientific literature, identified by a systematic literature review.

Atopic dermatitis (AD) is a chronic skin disease that significantly impacts patient quality of life (QoL). It is unknown whether patients and physicians have the same interpretation of AD burden. Unmet needs and AD disease burden were evaluated by comparing terminology used in social media with terminology used in scientific literature. AD terminology in social media was identified using the NetBase platform, and natural language processing was performed. Topics and words driving negative sentiment were evaluated overall and in relation to specific symptoms. The systematic review of scientific literature identified publications that included AD and QoL terms was identified from PubMed. Term analysis of titles and abstracts was conducted via natural language processing. The occurrence of topics and co-occurrence of words associated with QoL terms were evaluated. More than 3 million social media mentions (2018-2020) and 1519 scientific publications (2000-2020) were evaluated. There were more negative than positive social media mentions, and flare and pain were common symptoms driving negative sentiment. Face and hands were major drivers of negative sentiment in relation to AD symptoms in social media. Sleep and pain were often mentioned together. In scientific literature, pruritus and depression were the most frequently occurring symptoms. Similarly, pruritus was the most common AD symptom co-occurring with QoL terms in the assessed scientific literature. Social media analyses provide a unique view into the patient experience of AD. Symptoms driving negative sentiment in social media appear to be discordantly represented in scientific literature. Incorporating patient perspectives may improve disease understanding and management.

A case-comparison study of pregnant women with mitochondrial disease - what to expect?

OBJECTIVE: Mitochondrial disease is a disorder of energy metabolism that affects 1 in 4300 adults in the UK. Pregnancy is associated with physiological demands that have implications for energy metabolism. We were interested to know how pregnancy was affected in women with mitochondrial disease, particularly those with the most common pathogenic mutation m.3243A>G. DESIGN: Retrospective case-comparison study. POPULATION/SETTING: Sixty-seven women with genetically confirmed mitochondrial disease from the UK Mitochondrial Diseases Cohort and 69 unaffected women participated. METHODS: Participants answered questionnaires regarding each of their pregnancies. Patients were divided into two groups according to genetic mutation, with those harbouring m.3243A>G comprising a single group. MAIN OUTCOME MEASURES: Pregnancy-related complications, mode of delivery, gestational age and birthweight of newborns. RESULTS: Of 139 live births in the comparison group, 62 were in the m.3243A>G group and 87 were in the 'all other mutations' group. Pregnancies of women with the m.3243A>G mutation had significantly more gestational diabetes (odds ratio [OR] = 8.2, 95% CI 1.3-50.1), breathing difficulties (OR = 7.8, 95% CI 1.0-59.1) and hypertension (OR = 8.2, 95% CI 3.1-21.5) than the comparison group. Only half of the pregnancies in the m.3243A>G group had normal vaginal delivery, with emergency caesarean section accounting for 24.2% of deliveries. Babies were born significantly earlier to mothers harbouring m.3243A>G with 53.3% of them preterm (<37 weeks). These babies were also more likely to require resuscitation and admission. CONCLUSION: Women who carried the m.3243A>G mutation appeared to be at higher risk of complications during pregnancies, caesarean section and preterm delivery than the unaffected women or those with other forms of mitochondrial disease. TWEETABLE ABSTRACT: Pregnant women with mitochondrial disease - m.3243A>G mutation - are at greatly increased risk of complications and preterm delivery.

Topsoil porosity prediction across habitats at large scales using environmental variables.

Soil porosity and its reciprocal bulk density are important environmental state variables that enable modelers to represent hydraulic function and carbon storage. Biotic effects and their 'dynamic' influence on such state variables remain largely unknown for larger scales and may result in important, yet poorly quantified environmental feedbacks. Existing representation of hydraulic function is often invariant to environmental change and may be poor in some systems, particularly non-arable soils. Here we assess predictors of total porosity across two comprehensive national topsoil (0-15 cm) data sets, covering the full range of soil organic matter (SOM) and habitats (n = 1385 & n = 2570), using generalized additive mixed models and machine learning. Novel aspects of this work include the testing of metrics on aggregate size and livestock density alongside a range of different particle size distribution metrics. We demonstrate that porosity trends in Great Britain are dominated by biotic metrics, soil carbon and land use. Incorporating these variables into porosity prediction improves performance, paving the way for new dynamic calculation of porosity using surrogate measures with remote sensing, which may help improve prediction in data sparse regions of the world. Moreover, dynamic calculation of porosity could support representation of feedbacks in environmental and Earth System Models. Representing the hydrological feedbacks from changes in structural porosity also requires data and models at appropriate spatial scales to capture conditions leading to near-saturated soil conditions. Classification. Environmental Sciences.

Multiple soil map comparison highlights challenges for predicting topsoil organic carbon concentration at national scale.

Soil organic carbon (SOC) concentration is the fundamental indicator of soil health, underpinning food production and climate change mitigation. SOC storage is highly sensitive to several dynamic environmental drivers, with approximately one third of soils degraded and losing carbon worldwide. Digital soil mapping illuminates where hotspots of SOC storage occur and where losses to the atmosphere are most likely. Yet, attempts to map SOC often disagree. Here we compare national scale SOC concentration map products to reveal agreement of data in mineral soils, with progressively poorer agreement in organo-mineral and organic soils. Divergences in map predictions from each other and survey data widen in the high SOC content land types we stratified. Given the disparities are highest in carbon rich soils, efforts are required to reduce these uncertainties to increase confidence in mapping SOC storage and predicting where change may be important at national to global scales. Our map comparison results could be used to identify SOC risk where concentrations are high and should be conserved, and where uncertainty is high and further monitoring should be targeted. Reducing inter-map uncertainty will rely on addressing statistical limitations and including covariates that capture convergence of physical factors that produce high SOC contents.

Analytical modelling of soil porosity and bulk density across the soil organic matter and land-use continuum.

The thin layer of soil at the earth's surface supports life, storing water and nutrients for plant uptake. These processes occur in the soil pore space, often half the soil volume, but our understanding of how this volume responds to environmental change is poor. Convention, has been to predict soil porosity, or its reciprocal bulk density (BD), from soil texture using pedotransfer functions (PTFs). A texture based approach, invariant to environmental change, prevents feedback from land use or climate change to soil porosity. Moreover, PTFs are often limited to mineral soils with < 20% soil organic matter (SOM) content. Here, we develop an analytical model to predict soil porosity, or BD, as a function of SOM. We test it on two comprehensive, methodologically consistent, temperate national-scale topsoil data sets (0-15 cm) (Wales, n = 1385; Great Britain, n = 2570). The purpose of the approach is to generate an analytical function suitable for predicting soil porosity change with SOM content, while providing insight into the main grain-scale factors determining the porosity emergence. The newly developed function covering the entire SOM gradient allows for impacts of land use, management or climate change to feedback on soil porosity or bulk density through decadal dynamic changes in SOM.

Preoperative physical activity levels and postoperative pulmonary complications post-esophagectomy.

Postoperative pulmonary complications (PPCs) after esophagectomy have been reported to occur in 15-30% of patients and are the most common causes of major morbidity and mortality. Risk factors for the development of PPCs include impairment in lung function, cardiac reserve, aerobic capacity, and body composition. Physical activity is associated with these factors but has not been examined in relation to the risk of developing a PPC. The aim of this cross-sectional study was to investigate if there was a difference in physical activity levels, lung function, and body composition in patients who developed a PPC post-esphagectomy compared with those who did not. Consecutive patients were studied preoperatively: (i) lung function with a portable micro-medical spirometer; (ii) body composition analysis using a Tanita BC 418 machine (Tanita Corp., Tokyo, Japan); and (iii) physical activity with an accelerometer (RT3, (StayHealthy, Monrovia, CA, USA)). Thirty-seven patients were studied, mean age 61 ± 9 years. PPCs developed in 10 patients (27%). Smoking status, lung function, and body composition were similar in both groups. For physical activity, there were significant differences in the time spent sedentary (20.0 ± 1.5 h/day [PPC], 18.4 ± 2.1 h/day [non-PPC]; P < 0.05) and in moderate activity (20 ± 13.7 min/day [PPC], 36 ± 20.7 min/day [non PPC]; P < 0.01). Patients who developed a PPC engaged in less physical activity than those who did not; hence, targeting physical activity preoperatively may result in less PPCs.

Assessment of physical fitness for esophageal surgery, and targeting interventions to optimize outcomes.

This review examines how higher levels of physiological reserve and fitness can help the patient endure the demands of esophageal surgery. Lung function, body composition, cardiac function, inflammatory mediators and exercise performance are all determinants of fitness. Physical fitness, both as an independent risk factor and through its effect on other risk factors, has been found to be significantly associated with the risk of developing postoperative pulmonary complications (PPCs) in patients following esophagectomy. Respiratory dysfunction preoperatively poses the dominant risk of developing complications, and PPCs are the most common causes of morbidity and mortality. The incidence of PPCs is between 15 and 40% with an associated 4.5-fold increase in operative mortality leading to approximately 45% of all deaths post-esophagectomy. Cardiac complications are the other principal postoperative complications, and pulmonary and cardiac complications are reported to account for up to 70% of postoperative deaths after esophagectomy. Risk reduction in patients planned for surgery is key in attaining optimal outcomes. The goal of this review was to discuss the risk factors associated with the development of postoperative pulmonary complications and how these may be modified prior to surgery with a specific focus on the pulmonary complications associated with esophageal resection. There are few studies that have examined the effect of modifying physical fitness pre-esophageal surgery. The data to date would indicate a need to develop targeted interventions preoperatively to increase physical function with the aim of decreasing postoperative complications.

Non-EPI-DWI for Detection, Disease Monitoring, and Clinical Decision-Making in Thyroid Eye Disease.

BACKGROUND AND PURPOSE: The Clinical Activity Score is widely used to grade activity of thyroid eye disease and guide treatment decisions, but as a subjective measurement and being confined to the anterior orbit, it has limitations. Non-EPI-DWI of the extraocular muscles may offer advantages as a functional imaging technique with reduced skull base artifacts, but the correlation with the Clinical Activity Score and patient outcome is unknown. Our aim was to establish the correlation between the Clinical Activity Score and non-EPI-DWI and to describe the additional value provided by adjunctive non-EPI-DWI in making clinical decisions. MATERIALS AND METHODS: This was a retrospective longitudinal study of 31 patients seen in a multidisciplinary thyroid eye disease clinic during 5 years who had at least 1 ophthalmic and endocrine assessment including the Clinical Activity Score and a non-EPI-DWI ADC calculation. The Spearman rank correlation coefficient was used to determine the relationship between the Clinical Activity Score and non-EPI-DWI. A patient flow chart was constructed to evaluate clinical decision-making, and receiver operating characteristics were generated. RESULTS: From 60 non-EPI-DWI scans, 368 extraocular muscles were selected for analysis. There was a significant positive correlation between the Clinical Activity Score and ADC (r s = 0.403; 95% CI, 0.312-0.489; P < .001). ADC values were significantly higher in the Clinical Activity Score ≥ 3 group compared with the Clinical Activity Score < 3 group (P < .001). Our patient flow chart identified a third intermediate-severity cohort in which the non-EPI-DWI was particularly useful in guiding clinical decisions. CONCLUSIONS: The non-EPI-DWI correlated well with the Clinical Activity Score in our patients and was a useful adjunct to the Clinical Activity Score in making clinical decisions, especially in patients with intermediate activity and severity of thyroid eye disease.

Hypophosphatasia and the importance of the general dental practitioner - a case series and discussion of upcoming treatments.

Hypophosphatasia (HPP) is an inherited metabolic disorder that results in poorly mineralised bones and teeth. Clinical symptoms vary widely from mild dental anomalies to fatal fetal defects. The most common dental symptoms include exfoliation of the primary incisors before the age of three with little or no root resorption, large pulp chambers, alveolar bone loss and thin dentinal walls. There is generally minimal periodontal inflammation associated with the bony destruction and tooth loss. The general dental practitioner is usually the first clinician to spot signs of the milder forms of HPP. Patients diagnosed with dental symptoms in childhood can go on to develop significant morbidity in middle age with chronic bone pain and stress fractures of the long bones. The primary dental care clinician is the key to early diagnosis of such cases, whether they present in childhood or adulthood. Emerging enzyme replacement therapy has considerably changed the landscape of the disease, resulting in astonishing improvements in bone mineralisation and a significant reduction in mortality and morbidity. It is increasingly likely that primary and secondary care clinicians will treat patients with the severe forms of HPP, who would previously not have survived infancy.

Enterobacter agglomerans--associated cotton fever.

Cotton fever is usually a benign febrile, leukocytic syndrome of unknown etiology seen in intravenous narcotic abusers. Cotton and cotton plants are heavily colonized with Enterobacter agglomerans. We report a case of cotton fever associated with E agglomerans in which the organism was first isolated from the patient's blood and secondarily from cotton that he had used to filter heroin. Enterobacter agglomerans is with most probability the causal agent of cotton fever. Patients presenting with the classic history should have blood cultures performed and should be started on a regimen of empiric antibiotic therapy.

Motor nerve terminals on abdominal muscles in larval flesh flies, Sarcophaga bullata: comparisons with Drosophila.

Motor nerve terminals on abdominal body-wall muscles 6A and 7A in larval flesh flies were investigated to establish their general structural features with confocal microscopy, transmission electron microscopy, and freeze-fracture procedures. As in Drosophila and other dipterans, two motor axons supply these muscles, and two morphologically different terminals were discerned with confocal microscopy: thin terminals with relatively small varicosities (Type Is), and thicker terminals with larger varicosities (Type Ib). In serial electron micrographs, Type Ib terminals were distinguished from Type Is terminals by their larger cross-sectional area, more extensive subsynaptic reticulum, more mitochondrial profiles, and more clear synaptic vesicles. Type Ib terminals possessed larger synapses and more synaptic contact area per unit terminal length. Although presynaptic dense bars of active zones were similar in mean length for the two terminal types, there were almost twice as many dense bars per synapse for Type Ib terminals. Freeze-fractures through the presynaptic membrane showed particle-free areas indicative of synapses on the P-face, within which were localized aggregations of large intramembranous particles indicative of active zones. These particles were similar in number to those found at active zones of several other arthropod neuromuscular junctions. In general, synaptic structural parameters strongly paralleled those of the anatomically homologous muscles in Drosophila melanogaster. In live preparations, simultaneous focal recording from identified varicosities and intracellular recording indicated that the two terminals produced excitatory junction potentials of similar amplitude in a physiological solution similar to that used for Drosophila.

A novel and rapid method for culturing pure rat spinal cord astrocytes on untreated glass.

Astrocytes are the major population of glial cells, and are key players in the development, maintenance, and functioning of the central nervous system (CNS). Their potential as targets of therapeutic intervention following CNS injury makes the elucidation of their cellular and subcellular physiology a primary research goal. Well defined and pure cell culture systems are required to examine astrocytic physiology, biochemical pathways and underlying responses to pathophysiologically altered conditions. Previously published protocols for establishing primary astrocyte cultures are time- and resource-consuming or suffer high contamination from other undesired cell types. Here we describe a new and simple procedure for producing highly pure ( > 99%) rat primary astrocyte cultures. The method involves a simple mechanical dissociation of harvested spinal cord tissue through a porous membrane and the subsequent plating of the cells on plain, untreated glass coverslips. Astrocytes adhere very well to the untreated glass while other cell types require a substrate such as poly-L-lysine. The method described here is, therefore, ideal for experiments which require highly pure astrocyte cultures.

Evidence that endogenous enkephalins produce delta-opiate receptor mediated neuronal inhibitions in rat dorsal horn.

Kelatorphan, a full inhibitor of aminopeptidases, enkephalinase and dipeptidylaminopeptidase, enzymes which degrade the enkephalins, produced inhibitions (around 50%) of dorsal horn C fibre evoked responses in the rat, following local application. The inhibitions were reversed by the selective delta-opiate receptor antagonists ICI 174,864. Furthermore the inhibitions produced by two doses of Tyr-D-Ala-Gly-MePhe-Gly-ol (DAGO), a potent selective mu-opiate receptor agonist, were not altered in the presence of kelatorphan, so demonstrating an additive effect of the mu-agonist and the enzyme inhibitor. The inhibitions produced by the enzyme inhibitor would seem due to an increased availability of endogenous opioids, presumably the enkephalins which act via the delta-opiate receptor.

Group I and II metabotropic glutamate receptor expression in cultured rat spinal cord astrocytes.

We have examined the development of expression of group I and II metabotropic glutamate receptors (mGluRs) in pure rat spinal cord astrocyte cultures, using immunocytological and calcium imaging techniques. mGluR1alpha and mGluR2/3 antibodies were found to label roughly 10% of the total astrocyte population at all time points examined, whereas mGluR5 was poorly expressed in our culture system. Results from intracellular Ca2+ imaging experiments, measured using fura-2 ratio imaging, suggest that 20% of these cultured astrocytes express functional group I mGluRs (mGluR1 and/or 5). Our results contrast with previously published work in cultured cortical astrocytes where mGluR5 and not mGluR1 is expressed, suggesting that cultured astrocytes from different parts of the CNS exhibit different patterns of mGluR expression.

Wound botulism associated with black tar heroin.

The incidence of wound botulism is increasing and the epidemiology of the disease is changing. The majority of new cases are associated with injection drug use, in particular, the use of Mexican black tar heroin. This case report and discussion of wound botulism illustrate the following important points: Dysphagia, dysphonia, diplopia, and descending paralysis, in association with injection drug use, should alert the treating physician to the possibility of wound botulism. In such patients, the onset of respiratory failure may be sudden and without clinically obvious signs of respiratory weakness. For the reported patient, maximum inspiratory force measurements were the only reliable indicator of respiratory muscle weakness. This is a measurement not routinely performed in the ED, but may prove essential for patients with suspected wound botulism. To minimize the effect of the botulinum toxin and to decrease length of hospital stay, antitoxin administration and surgical wound debridement should be performed early.

Crack hands: a dermatologic effect of smoking crack cocaine.

We have seen multiple cases of a characteristic skin lesion produced by smoking crack cocaine. We describe a typical case with photographs demonstrating multiple blackened hyperkeratotic lesions of the palmar aspects of the fingers and palm, some linear, some circular. These involve mostly the dominant hand and are caused by the heat of the glass cocaine pipe.

Reversible blindness associated with alcoholic ketoacidosis: pseudomethanol intoxication.

We report a case of reversible blindness associated with severe acidosis. A 49-year-old female presented with sudden onset of bilateral blindness. A work up for possible etiologic factors including computed tomography failed to reveal any abnormalities except for ethanol induced severe ketoacidosis. Methanol was not detectable in the serum despite an ethanol level of 14.76 mmol/L, effectively ruling out the diagnosis of methanol intoxication. Treatment of the acidosis led to rapid resolution of her blindness. Review of the literature revealed two case reports of reversible blindness associated with severe acidosis in diabetics. The current case underscores the necessity for a clear understanding of the role of severe acidosis as the sole causative factor of reversible bilateral blindness.