ATI-1777, a Topical Jak1/3 Inhibitor, May Benefit Atopic Dermatitis without Systemic Drug Exposure: Results from Preclinical Development and Phase 2a Randomized Control Study ATI-1777-AD-201.

Introduction: Atopic dermatitis, a chronic, pruritic skin disease, affects 10-30% of children and up to 14% of adults in developed countries. ATI-1777, a potent and selective Jak1/3 inhibitor, was designed with multiple sites of metabolism to deliver local efficacy in the skin and limit systemic exposure. In preclinical studies, ATI-1777 selectively inhibited Jak1/3 with limited systemic exposure and without any adverse effects. Primary objective: The primary goal of this study was to assess the preliminary clinical efficacy of ATI-1777 topical solution in adults with moderate or severe atopic dermatitis. Design: ATI-1777-AD-201, a phase 2a, first-in-human, randomized, double-blind, vehicle-controlled, parallel-group study, evaluated the efficacy, safety, tolerability, and pharmacokinetics of ATI-1777 topical solution in 48 participants with atopic dermatitis over 4 weeks. Primary endpoint: The primary endpoint was a reduction of a modified Eczema Area and Severity Index score from baseline. Results: Reduction was significantly greater in the ATI-1777-treated group on day 28 than in vehicle-treated group (percentage reduction from baseline = 74.45% [standard error = 6.455] and 41.43% [standard error = 6.189], respectively [P < .001]). Average plasma concentrations of ATI-1777 were <5% of the half-maximal inhibitory concentration of ATI-1777 for inhibiting Jak1/3. No deaths or serious adverse events were reported. Conclusion: Topical ATI-1777 does not lead to pharmacologically relevant systemic drug exposure and may reduce clinical signs of atopic dermatitis. Trial Registration: The study was registered at ClinicalTrials.gov with the number NCT04598269.

People who use drugs show no increase in pre-existing T-cell cross-reactivity toward SARS-CoV-2 but develop a normal polyfunctional T-cell response after standard mRNA vaccination.

People who use drugs (PWUD) are at a high risk of contracting and developing severe coronavirus disease 2019 (COVID-19) and other infectious diseases due to their lifestyle, comorbidities, and the detrimental effects of opioids on cellular immunity. However, there is limited research on vaccine responses in PWUD, particularly regarding the role that T cells play in the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we show that before vaccination, PWUD did not exhibit an increased frequency of preexisting cross-reactive T cells to SARS-CoV-2 and that, despite the inhibitory effects that opioids have on T-cell immunity, standard vaccination can elicit robust polyfunctional CD4+ and CD8+ T-cell responses that were similar to those found in controls. Our findings indicate that vaccination stimulates an effective immune response in PWUD and highlight targeted vaccination as an essential public health instrument for the control of COVID-19 and other infectious diseases in this group of high-risk patients.

Incremental Density-Based Clustering on Multicore Processors.

The density-based clustering algorithm is a fundamental data clustering technique with many real-world applications. However, when the database is frequently changed, how to effectively update clustering results rather than reclustering from scratch remains a challenging task. In this work, we introduce IncAnyDBC, a unique parallel incremental data clustering approach to deal with this problem. First, IncAnyDBC can process changes in bulks rather than batches like state-of-the-art methods for reducing update overheads. Second, it keeps an underlying cluster structure called the object node graph during the clustering process and uses it as a basis for incrementally updating clusters wrt. inserted or deleted objects in the database by propagating changes around affected nodes only. In additional, IncAnyDBC actively and iteratively examines the graph and chooses only a small set of most meaningful objects to produce exact clustering results of DBSCAN or to approximate results under arbitrary time constraints. This makes it more efficient than other existing methods. Third, by processing objects in blocks, IncAnyDBC can be efficiently parallelized on multicore CPUs, thus creating a work-efficient method. It runs much faster than existing techniques using one thread while still scaling well with multiple threads. Experiments are conducted on various large real datasets for demonstrating the performance of IncAnyDBC.

Substrate-based kinase activity inference identifies MK2 as driver of colitis.

Inflammatory bowel disease (IBD) is a chronic and debilitating disorder that has few treatment options due to a lack of comprehensive understanding of its molecular pathogenesis. We used multiplexed mass spectrometry to collect high-content information on protein phosphorylation in two different mouse models of IBD. Because the biological function of the vast majority of phosphorylation sites remains unknown, we developed Substrate-based Kinase Activity Inference (SKAI), a methodology to infer kinase activity from phosphoproteomic data. This approach draws upon prior knowledge of kinase-substrate interactions to construct custom lists of kinases and their respective substrate sites, termed kinase-substrate sets that employ prior knowledge across organisms. This expansion as much as triples the amount of prior knowledge available. We then used these sets within the Gene Set Enrichment Analysis framework to infer kinase activity based on increased or decreased phosphorylation of its substrates in a dataset. When applied to the phosphoproteomic datasets from the two mouse models, SKAI predicted largely non-overlapping kinase activation profiles. These results suggest that chronic inflammation may arise through activation of largely divergent signaling networks. However, the one kinase inferred to be activated in both mouse models was mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2 or MK2), a serine/threonine kinase that functions downstream of p38 stress-activated mitogen-activated protein kinase. Treatment of mice with active colitis with ATI450, an orally bioavailable small molecule inhibitor of the MK2 pathway, reduced inflammatory signaling in the colon and alleviated the clinical and histological features of inflammation. These studies establish MK2 as a therapeutic target in IBD and identify ATI450 as a potential therapy for the disease.

Diabetic and non-diabetic patients report equal symptom relief after arthroscopic capsular release of frozen shoulder.

BACKGROUND: Frozen shoulder is a painful joint disease. Patients with diabetes seem to have worse clinical symptoms and surgery in this patient population is believed to be more common.The objective postoperative evaluation indicates inferior results when surgically treating diabetics, but no previous studies have investigated exclusively the subjective patient satisfaction with arthroscopic capsular release. MATERIALS AND METHODS: A total of 93 patients were included. All had persistent symptoms despite conservative treatment for at least six months. The patients were retrospectively divided into two groups based on diabetes status: Group 1 consisted of patients with type 1 or type 2 diabetes (18) and group 2 consisted of the remaining patients (75). Evaluation was performed prior to arthroscopic capsular release and at six months follow-up. The web-based questionnaire consisted of two different evaluation forms: The Oxford Shoulder Score (OSS) and a visual quality scale (VQS). RESULTS: Both groups reported a statistically significant improvement in both evaluations. OSS in group 1 improved by 11.5 [95% CI: 6.2 ; 16.4] and by 15.8 [95% CI: 13.6 ; 17.9] in group 2. The improvement was more pronounced in group 2, though not statistically significant (p = 0.09). The VQS improved 39.6 in group 1 and 44.5 in group 2, (p = 0.50). CONCLUSION: Diabetic and non-diabetic patients reported equal symptom relief after arthroscopic capsular release of frozen shoulder when selected for operation without considering diabetic status. We will continue to select patients for arthroscopic release without differences in preoperative counseling between diabetics and non-diabetics.

The LASSO Program in Oslo: Harm Reduction Using Buprenorphine-Naloxone (Suboxone®) in a Low Threshold Setting.

BACKGROUND: This is a 6-year retrospective quality control study of the LASSO Program (Low Threshold Substitution Treatment in Oslo), using exclusively Suboxone® (buprenorphine-naloxone [BPNX]) in out-patient settings. Adequate abstinence prior to induction is necessary to avoid acute onset opioid withdrawal symptoms; thus, its use in low threshold settings is far less common than methadone. OBJECTIVES: The aim of this study was to determine if BPNX is a safe and feasible medication to use in a low threshold setting. METHODS: The analysis is based on daily supervised BPNX medication. The standardized induction regime started with 4-mg BPNX increasing by 4 mg daily until 16 mg, with individual adjustments based on clinical status. Treatment effect was evaluated by the number of medication induction attempts, treatment length and lag time between initial contact and medication start. Statistical computations were performed with SPSS®. RESULTS: There were 331 out of 394 registered patient inquires that started on BPNX. Two hundred fifty-three patients (76.4%) completed induction on first attempt with 95% Wilson score CIs of (0.716-0.807). The accumulated percentage increased to 85.2% during successive inductions. No significant association was found between lag time and (i) the number of days on medication during the first induction; or (ii) total treatment length. Patients had a median lag time of 5 days, remained in treatment a median of 52.0 days with an average of 3.9 inductions. There were no cases of severe precipitated withdrawal and only 2 cases of adverse reactions among the 1,293 inductions and 25,544 administered dosages. CONCLUSION: This study shows that BPNX is highly effective in treating marginalized heroin addicts in low threshold settings. Even during their first attempt, 76.4% completed induction. There were no cases of severe precipitated withdrawal. Prolonged lag time affected neither the length of first treatment nor the total treatment length. Individualized induction readiness approach and motivation were central to the above results.

Acromioplasty in patients selected for operation by national guidelines.

BACKGROUND: Shoulder impingement syndrome is the most common shoulder disorder. Even though conservative treatment is the primary treatment of choice, surgery has increased substantially in several countries during the last 20 years. This has resulted in recommended clinical guidelines for treatment of shoulder impingement syndrome in countries such as The Netherlands and Denmark during recent years. The aim of this study was to investigate the effectiveness of an arthroscopic subacromial decompression in 244 patients selected for surgery according to national clinical guidelines. MATERIALS AND METHODS: Patients were included from an Internet-based shoulder and elbow database. They were asked to complete 2 questionnaires consisting of the Oxford Shoulder Score (OSS) and the EuroQol 5-Dimension 3-Level and visual analog scale preoperatively and at 6-month follow-up. All patients were carefully selected for surgery according to the national guidelines, with symptoms persisting for at least 6 months. Furthermore, subgroups related to the OSS were formed to assess the clinical outcome according to preoperative status and age. RESULTS: For the complete study group, an OSS change of 10 (8.8-11.2; P = .0001) was found at 6-month follow-up. No significant difference was found between the genders (P = .17). The largest clinical effect from the intervention was found in the low preoperative OSS (pre-OSS) group, in which a mean change of 17 was found. The moderate and high pre-OSS groups had mean changes of 13 and 5, respectively. Similarly, according to the EuroQol 5-Dimension 3-Level and visual analog scale, the largest improvements were seen in the low and moderate pre-OSS groups. CONCLUSION: Arthroscopic subacromial decompression is a valid treatment, reducing pain and improving quality of life for patients selected for surgery according to the Danish national guidelines.

Integrodifference models for persistence in temporally varying river environments.

To fully understand population persistence in river ecosystems, it is necessary to consider the effect of the water flow, which varies tremendously with seasonal fluctuations of water runoff and snow melt. In this paper, we study integrodifference models for growth and dispersal in the presence of advective flow with both periodic (alternating) and random kernel parameters. For the alternating kernel model, we obtain the principal eigenvalue of the linearization operator to determine population persistence and derive a boundary value problem to calculate it. For the random model, we establish two persistence metrics: a generalized spectral radius and the asymptotic growth rate, which are mathematically equivalent but can be understood differently, to determine population persistence or extinction. The theoretical framework and methods for calculations are provided, and the framework is applied to calculating persistence in highly variable river environments.

The addition of lidocaine to bupivacaine does not shorten the duration of spinal anesthesia: a randomized, double-blinded study of patients undergoing knee arthroscopy.

BACKGROUND: The duration of spinal anesthesia with bupivacaine is often too long for day surgery. A recent study of patients presenting for transurethral surgery suggested that the addition of a small amount of lidocaine to intrathecal hyperbaric bupivacaine could shorten the duration of the sensory and motor blocks. In this prospective, randomized double-blind study we investigated these findings in patients undergoing unilateral knee arthroscopy. METHODS: Fifty patients were randomized to receive 2 mL hyperbaric 0.5% bupivacaine plus either 0.6 mL 1% lidocaine (lidocaine group) or 0.6 mL saline (control group). The sensory and motor blocks were monitored until complete regression and the patient was ready for discharge. The patients were interviewed 2 and 7 days after the operation about any side effects and any signs of transient neurologic syndrome. RESULTS: Data on 45 patients were available for analysis (24 in the lidocaine group). There was no statistically significant difference between the groups regarding time to readiness for surgery, maximum level of sensory block, total duration of sensory, and motor blocks or time to discharge from the postoperative care unit. Two patients in the control group and 1 patient in the study group had symptoms of transient neurologic syndrome for <24 hours after the operation. One patient had voiding difficulties for 3 days. All symptoms resolved spontaneously. No patient had spinal headache or backache. CONCLUSION: We did not confirm, in patients undergoing knee arthroscopy, that the addition of a small dose of lidocaine to intrathecal hyperbaric bupivacaine could shorten the duration of sensory or motor blocks or time to readiness for discharge from the postanesthesia care unit.

Effect of perioperative beta blockade in patients with diabetes undergoing major non-cardiac surgery: randomised placebo controlled, blinded multicentre trial.

OBJECTIVES: To evaluate the long term effects of perioperative beta blockade on mortality and cardiac morbidity in patients with diabetes undergoing major non-cardiac surgery. DESIGN: Randomised placebo controlled and blinded multicentre trial. Analyses were by intention to treat. SETTING: University anaesthesia and surgical centres and one coordinating centre. PARTICIPANTS: 921 patients aged > 39 scheduled for major non-cardiac surgery. INTERVENTIONS: 100 mg metoprolol controlled and extended release or placebo administered from the day before surgery to a maximum of eight perioperative days. MAIN OUTCOME MEASURES: The composite primary outcome measure was time to all cause mortality, acute myocardial infarction, unstable angina, or congestive heart failure. Secondary outcome measures were time to all cause mortality, cardiac mortality, and non-fatal cardiac morbidity. RESULTS: Mean duration of intervention was 4.6 days in the metoprolol group and 4.9 days in the placebo group. Metoprolol significantly reduced the mean heart rate by 11% (95% confidence interval 9% to 13%) and mean blood pressure by 3% (1% to 5%). The primary outcome occurred in 99 of 462 patients in the metoprolol group (21%) and 93 of 459 patients in the placebo group (20%) (hazard ratio 1.06, 0.80 to 1.41) during a median follow-up of 18 months (range 6-30). All cause mortality was 16% (74/462) in the metoprolol group and 16% (72/459) in the placebo group (1.03, 0.74 to 1.42). The difference in risk for the proportion of patients with serious adverse events was 2.4% (- 0.8% to 5.6%). CONCLUSIONS: Perioperative metoprolol did not significantly affect mortality and cardiac morbidity in these patients with diabetes. Confidence intervals, however, were wide, and the issue needs reassessment. TRIAL REGISTRATION: Current Controlled Trials ISRCTN58485613.

Aza-cope rearrangement-mannich cyclizations for the formation of complex tricyclic amines: stereocontrolled total synthesis of (+/-)-gelsemine.

A detailed examination of the use of aza-Cope rearrangement-Mannich cyclization sequences for assembling the azatricyclo[4.4.0.0(2,8)]decane core of gelsemine is described. Iminium ions and N-acyloxyiminium ions derived from endo-oriented 1-methoxy- or 1-hydroxybicyclo[2.2.2]oct-5-enylamines do not undergo the first step of this sequence, cationic aza-Cope rearrangement, to form cis-hydroisoquinolinium ions. However, the analogous base-promoted oxy-aza-Cope rearrangement does take place to form cis-hydroisoquinolones containing functionality that allows iminium ions or N-acyloxyiminium ions to be generated regioselectively in a subsequent step. Mannich cyclization of cis-hydroisoquinolones prepared in this way efficiently assembles the azatricyclo[4.4.0.0(2,8)]decane unit of gelsemine. Using a sequential base-promoted oxy-aza-Cope rearrangement/Mannich cyclization sequence, gram quantities of azatricyclo[4.4.0.0(2,8)]decanone 18, a central intermediate in our total of (+/-)-gelsemine, were prepared from 3-methylanisole in 12 steps and 16% overall yield.