Genetic therapies and respiratory outcomes in patients with neuromuscular disease.

PURPOSE OF REVIEW: Genetic therapies made a significant impact to the clinical course of patients with spinal muscular atrophy and Duchenne muscular dystrophy. Clinicians and therapists who care for these patients want to know the changes in respiratory sequelae and implications for clinical care for treated patients. RECENT FINDINGS: Different genetic therapy approaches have been developed to replace the deficient protein product in spinal muscular atrophy and Duchenne muscular dystrophy. The natural history of these conditions needed to be understood in order to design clinical trials. Respiratory parameters were not the primary outcome measures for the clinical trials. The impact of these therapies is described in subsequent clinical trial reports or real-world data. SUMMARY: Genetic therapies are able to stabilize or improve the respiratory sequelae in patients with spinal muscular atrophy and Duchenne muscular dystrophy. Standardized reporting of these outcomes is needed to help inform the future revisions of clinical standards of care and practice guidelines.

Safety, pharmacodynamics, and antiviral activity of selgantolimod in viremic patients with chronic hepatitis B virus infection.

Background & Aims: Novel finite therapies for chronic hepatitis B (CHB) are needed, since lifelong treatment is usually required with current available oral antivirals. This phase II study (NCT03615066) evaluated the safety, pharmacodynamics, and antiviral activity of selgantolimod (a Toll-like receptor 8 agonist [TLR8]) with tenofovir alafenamide (TAF). Methods: Viremic patients with CHB not receiving treatment were stratified by HBeAg status and randomized 2:2:1 to TAF 25 mg/day with selgantolimod 3 mg orally once weekly (QW), selgantolimod 1.5 mg QW, or placebo. Combination therapy continued until week (W)24, followed by TAF monotherapy until W48; patients then discontinued TAF and were followed until W96 (treatment-free follow-up [TFFU] period). The primary efficacy endpoint was the proportion with ≥1 log10 IU/ml HBsAg decline at W24. Results: Sixty-seven patients received study drug; 27 were followed during TFFU. Nausea, headache, vomiting, fatigue, and dizziness were the most common adverse events. Most adverse events were grade 1. Alanine aminotransferase flares were not observed up to W48. Four patients experienced alanine aminotransferase and hepatitis flares during TFFU; all had HBV DNA increases. Selgantolimod increased serum cytokines and chemokines and redistributed several circulating immune cell subsets. No patients achieved the primary efficacy endpoint. Mean HBsAg changes were -0.12, -0.16, and -0.12 log10 IU/ml in the selgantolimod 3 mg, selgantolimod 1.5 mg, and placebo groups, respectively, at W48; HBV DNA declined in all groups by ≥2 log10 IU/ml as early as W2, with all groups rebounding to baseline during TFFU. No HBsAg or HBeAg loss or seroconversion was observed throughout TFFU. Conclusions: Selgantolimod up to 3 mg was safe and well tolerated. Pharmacodynamics and antiviral activity in viremic patients support continued study of selgantolimod in combination CHB therapies. Impact and implications: Novel therapeutics for chronic HBV infection are needed to achieve a functional cure. In this study, we confirmed the safety and tolerability of selgantolimod (formerly GS-9688, a TLR8) when administered with tenofovir alafenamide over 24 weeks in viremic patients with chronic HBV infection. Overall, declines in HBsAg levels with selgantolimod treatment were modest; subgroup analysis indicated that patients with alanine aminotransferase levels greater than the upper limit of normal had significantly greater declines compared to those with normal alanine aminotransferase levels (-0.20 vs. -0.03 log10 IU/ml; p <0.001). These findings suggest a potential differential response to selgantolimod based on patients' baseline HBV-specific immune response, which should be considered in future investigations characterizing the underlying mechanisms of selgantolimod treatment and in HBV cure studies using similar immunomodulatory pathways. Clinical trial number: NCT03615066 be found at https://www.gileadclinicaltrials.com/transparency-policy/.

A core domain set for pyoderma gangrenosum trial outcomes: an international eDelphi and consensus study from the UPGRADE initiative.

BACKGROUND: Pyoderma gangrenosum (PG) is a rare ulcerative skin condition with no current standardized outcomes or outcome measures. With a rich investigational therapeutic pipeline, standardization of outcomes and improvement of data quality and interpretability will promote the appropriate and consistent evaluation of potential new therapies. Core outcome sets (COS) are agreed, standardized sets of outcomes that represent the minimum that should be measured and reported in all clinical trials of a specific condition. OBJECTIVES: To identify and reach a consensus on which domains (what to be measured) should be included in the Understanding Pyoderma Gangrenosum: Review and Analysis of Disease Effects (UPGRADE) core domain set for clinical trials in PG. METHODS: Collaborative discussions between patients and PG experts, and a systematic review of the literature identified items and prospective domains. A three-round international eDelphi exercise was performed to prioritize the domains and refine the provisional items (consensus: ≥ 70% of participants rating a domain as 'extremely important' and < 15% of participants voting 'not important'), followed by an international meeting to reach consensus on the core domain set (consensus: < 30% disagreement). Item-generation discussions and consensus meetings were hosted via online videoconferences. The eDelphi exercise and consensus voting were performed using Qualtrics survey software. Participants were adults with PG, healthcare professionals, researchers and industry representatives. RESULTS: Collaborative discussions and systematic reviews yielded 115 items, which were distilled into 15 prospective domains. The eDelphi exercise removed the three lowest-priority domains ('laboratory tests', 'treatment costs' and 'disease impact on family') and ranked 'pain', 'quality of life' and 'physical symptoms' as the highest-priority prospective domains. Consensus was reached on the domains of 'pain', 'quality of life' and 'clinical signs'. The domain of 'disease course/disease progression' narrowly failed to reach consensus for inclusion in the core set (32% of participants voted 'no'). Refinement of this domain definition will be required and presented for consideration at future consensus meetings. CONCLUSIONS: The UPGRADE core domain set for clinical trials in PG has been agreed by international multistakeholder consensus. Future work will develop and/or select outcome measurement instruments for these domains to establish a COS.

Safety and efficacy of the oral TLR8 agonist selgantolimod in individuals with chronic hepatitis B under viral suppression.

BACKGROUND & AIMS: Selgantolimod (GS-9688) is a Toll-like receptor 8 (TLR8) agonist that suppresses HBV in vitro. In a phase II study, we evaluated the safety and efficacy of weekly selgantolimod treatment in virally suppressed individuals with chronic HBV taking oral antiviral treatment. METHODS: Forty-eight patients were randomized into two cohorts (hepatitis B e antigen [HBeAg]-positive and -negative [n = 24 each]) to receive oral selgantolimod 3 mg, 1.5 mg, or placebo (2:2:1) once weekly for 24 weeks while maintaining oral antivirals. The primary efficacy endpoint was the percentage of patients with a ≥1 log10 IU/ml decline in hepatitis B surface antigen (HBsAg) from baseline to week 24. Post-treatment, patients continued on oral antivirals for 24 weeks. RESULTS: The primary endpoint was reached by one participant, who was HBeAg-negative and received selgantolimod 1.5 mg. In contrast with placebo-treated patients (n = 9), only selgantolimod-treated patients (n = 39 total) had HBsAg declines greater than 0.1 log10 IU/ml at weeks 24 (18%, 7/39) and 48 (26%, 10/39), HBsAg loss (5%, 2/39 through 48 weeks), or HBeAg loss (16%, 3/19 through 48 weeks). The most common adverse events in selgantolimod-treated groups were nausea (46%), upper respiratory tract infection (23%), and vomiting (23%). Gastrointestinal disorders were mostly mild and transient. Selgantolimod induced transient dose-dependent increases in serum cytokines, including IL-12p40, IFN-γ, and IL-1RA, as well as rapid redistribution of some circulating immune cell subsets. CONCLUSION: Oral selgantolimod up to 3 mg once weekly for 24 weeks was generally safe and well tolerated and led to serologic changes associated with progression to durable cure in two individuals by week 48. GOV IDENTIFIER: NCT03491553. IMPACT AND IMPLICATIONS: The only robust criterion for stopping treatment in chronic hepatitis B is loss of hepatitis B surface antigen (known as functional cure), which is rare during nucleos(t)ide analogue therapy. It is likely that novel antiviral and immunomodulatory therapies will be needed to achieve finite functional cure. Selgantolimod is an oral Toll-like receptor 8 agonist that has shown antiviral activity in vitro as well as safety in a phase I clinical trial with weekly dosing. In this phase II study, selgantolimod therapy was associated with transient increases in serum cytokines, rapid redistribution of circulating immune cell subsets, modest reductions in HBsAg and HBeAg levels, and occasional loss of HBsAg (5%) and HBeAg (16%) among participants with chronic hepatitis B on nucleos(t)ide analogue therapy with viral suppression. Our results support continued development of selgantolimod as a component of a future hepatitis B cure regimen.

Bio-Inspired Sutures: Simulating the Role of Suture Placement in the Mechanical Response of Interlocking Structures.

The hardest anatomical components of many animals are connected at thin seams known as sutures, which allow for growth and compliance required for respiration and movement and serve as a defense mechanism by absorbing energy during impacts. We take a bio-inspired approach and parameterize suture geometries to utilize geometric connections, rather than new engineering materials, to absorb high-impact loads. This study builds upon our work that investigated the effects of the dovetail suture contact angle, tangent length, and tab radius on the stiffness and toughness of an archway structure using finite element analysis. We explore how increasing the archway segmentation affects the mechanical response of the overall structure and investigate the effects of displacement when induced between sutures. First, when keeping displacement along a suture but increasing the number of archway pieces from two to four, we observed that stiffness and toughness were reduced substantially, although the overall trends stayed the same. Second, when the displacement was induced along an archway edge rather than upon a suture (in a three-piece archway), we observed that archway stiffness and toughness were much less sensitive to the changes in the suture parameters, but unlike the archway indented along the suture line, they tended to lose stiffness and toughness as the tangent length increased. This study is a step forward in the development of bio-inspired impact-resistant helmets.

Minimum data set for treatment effectiveness in pyoderma gangrenosum (MIDSTEP): an international protocol of an e-Delphi study to develop a clinical physician-driven treatment effectiveness registry on behalf of the UPGRADE initiative.

Pyoderma gangrenosum (PG) is a rare inflammatory condition with an immense disease burden that remains understudied. With limited approved treatments and low-quality clinical evidence, PG continues to have poor patient outcomes. Unfortunately, improvement in PG treatments and patient care is based on additional research endeavors that can only be developed from existing high-quality data. The following protocol outlines the development of the Minimum Data Set for Treatment Effectiveness in Pyoderma gangrenosum (MIDSTEP), a core set of domains and domain items for the Pyoderma Gangrenosum Treatment Effectiveness (PyGaTE) international registry. The outcomes and benefits are focused on providing real-world data for physicians to improve their clinical decisions on PG treatment and inform clinical trial design, promoting clinical research among the international scientific community. MIDSTEP is a multi-phase project. The first phase will produce a domain item list from a literature review to take into the second phase which would finalize the core data set by an e-Delphi exercise. There will be a single stakeholder group participating together in the e-Delphi consisting of PG experts (healthcare providers, researchers, methodologists, industry representatives, and regulators), ulcerative PG patients, and PG patient advocates. The methodology outlined in the protocol is a systematic method based on several guidelines through COMET and established dermatologic registries and outcome sets with systematic methodologies of their own. The third phase will identify the instruments for the items, the 'when to measure' the items, and the platform for the registry. The last phase is the implementation and continued maintenance of the international registry PyGaTE. By solidifying a consensus on standardized outcomes and collecting information on PG treatment effectiveness in a centralized database, existing treatments can be compared more systematically and analyzed with increased evidence. MIDSTEP and the PyGaTE international registry will have the ambitious goal to generate and disseminate real-world data that can be used by all stakeholders to improve health outcomes for PG patients. Future potential for the outcome of this project includes the development of a gold-standard PG treatment.

Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma.

BACKGROUND: Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease. METHODS: In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician's choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival. RESULTS: A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell-associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T-related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%). CONCLUSIONS: A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies. (Funded by Janssen and Legend Biotech; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.).

Tests and classification methods in adaptive designs with applications.

Statistical tests for biomarker identification and classification methods for patient grouping are two important topics in adaptive designs of clinical trials related to genomic studies. In this article, we evaluate four test methods for biomarker identification in the first stage of an adaptive design: a model-based identification method, the popular two-sided t-test, the nonparametric Wilcoxon Rank-Sum test (two-sided), and the Regularized Generalized Linear Models. For patients grouping in the second stage, we examine classification methods such as Random Forest, Elastic-net Regularized Generalized Linear Models, Support Vector Machine (SVM), Gradient Boosting Machine (GBM), and Extreme Gradient Boosting (XGBoost). Simulation studies are carried out to assess the performance of the different methods. The best identification methods are chosen based on the well-known F 1 score, while the best classification techniques are selected based on the area under a receiver operating characteristic curve (AUC). The chosen methods are then applied to the Adaptive Signature Design (ASD) with a real data set from breast cancer patients for the purpose of evaluating the performance of ASD in different situations.

Longitudinal liver sampling in patients with chronic hepatitis B starting antiviral therapy reveals hepatotoxic CD8+ T cells.

Accumulation of activated immune cells results in nonspecific hepatocyte killing in chronic hepatitis B (CHB), leading to fibrosis and cirrhosis. This study aims to understand the underlying mechanisms in humans and to define whether these are driven by widespread activation or a subpopulation of immune cells. We enrolled CHB patients with active liver damage to receive antiviral therapy and performed longitudinal liver sampling using fine-needle aspiration to investigate mechanisms of CHB pathogenesis in the human liver. Single-cell sequencing of total liver cells revealed a distinct liver-resident, polyclonal CD8+ T cell population that was enriched at baseline and displayed a highly activated immune signature during liver damage. Cytokine combinations, identified by in silico prediction of ligand-receptor interaction, induced the activated phenotype in healthy liver CD8+ T cells, resulting in nonspecific Fas ligand-mediated killing of target cells. These results define a CD8+ T cell population in the human liver that can drive pathogenesis and a key pathway involved in their function in CHB patients.

The "Understanding Pyoderma Gangrenosum, Review and Assessment of Disease Effects (UPGRADE)" Project: a protocol for the development of the core outcome domain set for trials in pyoderma gangrenosum.

INTRODUCTION: Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis that affects approximately 0.3-6 out of every 100,000 people worldwide. Clinical trials are scarce but there is growing interest in using newer and more targeted therapeutics to achieve disease remission. However, there are no standardized instruments to measure outcomes in PG and, therefore, future clinical trials are hampered by the absence of established and accurate means of assessment and comparison. Therefore, we aim to produce an internationally accepted core outcome set (COS) that will overcome this obstacle. This protocol outlines our intended approach to achieve the first part of this process, establishing a core outcome domain set. METHODS: An international team of PG stakeholders, consisting of physicians, wound care nurses, patients, scientists and industry representatives, has been assembled for the purpose of building a comprehensive and universally established set of core outcome domains. During the first step, we will generate items of relevance using a nominal process from all stakeholders. Items will be distilled and collapsed into potential domains and subdomains. A systematic review of current methods for reporting PG has already been published and domains identified in this work will be considered in the generation of the core domains set. During the second step, after the potential domains and subdomains are identified, stakeholders will participate in an e-Delphi exercise to rate the importance of (sub)domains. A final consensus meeting will be organized with the goal of establishing a core domain set. CONCLUSION: Pyoderma gangrenosum lacks an established COS and previously published clinical trials have used inconsistent measures established from similarly inconsistent domains. As a first step this study seeks to create a core domain set within the COS, to build the foundation for future core outcome work for PG.

Phase II, Open-Label Study of Ciltacabtagene Autoleucel, an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor-T-Cell Therapy, in Chinese Patients With Relapsed/Refractory Multiple Myeloma (CARTIFAN-1).

PURPOSE: CARTIFAN-1 aimed to evaluate the efficacy and safety of ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen-targeting chimeric antigen receptor T-cell therapy, in Chinese patients with relapsed/refractory multiple myeloma (RRMM). METHODS: This pivotal phase II, open-label study (ClinicalTrials.gov identifier: NCT03758417), conducted across eight sites in China, enrolled adult patients with RRMM who had received ≥ 3 lines of prior therapy, including a proteasome inhibitor and immunomodulatory drug. Patients received a single infusion of cilta-cel (target dose 0.75 × 106 chimeric antigen receptor-positive viable T cells/kg). The primary end point was overall response rate. Secondary end points included progression-free survival (PFS), overall survival (OS), and incidence and severity of adverse events (AEs). RESULTS: As of the clinical cutoff of July 19, 2021, 48 patients received a cilta-cel infusion. At an 18-month median follow-up, the overall response rate was 89.6% (95% CI, 77.3 to 96.5), with a median time to first response of approximately 1 month; 77.1% of patients (95% CI, 62.7 to 88.0) achieved complete response or better. Medians for duration of response, PFS, and OS were not reached. The 18-month PFS and OS rates were 66.8% (95% CI, 49.4 to 79.4) and 78.7% (95% CI, 64.0 to 88.0), respectively. Hematologic AEs were common, including anemia (100%), neutropenia (97.9%), lymphopenia (95.8%), and thrombocytopenia (87.5%). Cytokine release syndrome occurred in 97.9% of patients (35.4% grade 3/4); the median time to onset was 7 days, and the median duration was 5 days. Infections occurred in 85.4% of patients (37.5% grade 3/4). Ten deaths occurred after cilta-cel infusion, eight of which were due to treatment-related AEs. CONCLUSION: These data demonstrate a favorable risk-benefit profile for a single infusion of cilta-cel, resulting in early, deep, and durable responses in heavily pretreated patients with RRMM in China.

Systematic review and meta-analysis of the efficacy of gabapentin in chronic female pelvic pain without another diagnosis.

Background: While widely used for the treatment of chronic pelvic pain, limited data exists on efficacy of gabapentin, especially in the subgroup of women suffering from chronic pelvic pain without a known diagnosis, such as endometriosis. Objective: This study aimed to assess the efficacy of gabapentin when administered to women with chronic pelvic pain without another diagnosis. Study Design: We performed a Systematic Review and Meta Analysis including all controlled clinical trials addressing the use of gabapentin for the treatment of chronic pelvic pain without another diagnosis. We searched PubMed, Scopus, Web of Science, ClinicalTrials.Gov, MEDLINE, and The Cochrane Library from inception of each database to April 30, 2021. We included all the studies that fulfilled the following criteria: (1) population: women suffering from chronic pelvic pain without another identified diagnosis (such as endometriosis); (2) intervention: gabapentin (regardless of the dosage); (3) comparator:placebo; (4) outcomes: pain score (visual analog scale) after 3 months and pain score (visual analog scale) after 6 months as primary outcomes; and (5) study design: we only included randomized or controlled clinical trials. Our exclusion criteria included (1) uncontrolled clinical trials, (2) studies that did not report data or measures for any of our selected outcomes, (3) studies that included patients with surgically or clinically diagnosed endometriosis, or (4) studies with no full-text manuscript available. Risk of bias assessment was performed using the Cochrane risk of bias tool. We analyzed dichotomous outcomes as percentages and totals, whereas continuous outcomes were analyzed using mean difference, standard deviations, and relative 95% confidence intervals using the inverse variance method. Results: We included 4 placebo-controlled randomized controlled trials. Analysis was hindered because half of the studies (n=2) used the visual analog scale pain score and the other half (n=2) used the numerical rating scale. The analysis showed that when compared with the placebo, gabapentin significantly lowered the visual analog scale pain score at 3 months (mean difference, 0.79; 1.23 to 0.35; P=.005) and 6 months (mean difference, 1.68; 2.30 to 1.05; P=.001) and the numerical rating scale pain score at 3 months (mean difference, 0.20; 0.25 to 0.15; P=.001). However, in terms of the numerical rating scale pain score after 6 months, the 2 groups showed no significant difference (mean difference, 0.27; 0.80 to 0.26; P=.32). CONCLUSION: Gabapentin may hold benefit for the management of chronic pelvic pain, with significant improvement in pain seen in both scales at 3 months when compared with the placebo, but only in the visual analog scale group at 6 months of usage. Secondary to the differences in the nature of the 2 scales, a further weighted combined analysis was not possible.

Bio-Inspired Sutures: Using Finite Element Analysis to Parameterize the Mechanical Response of Dovetail Sutures in Simulated Bending of a Curved Structure.

Many animals have protective anatomical structures that allow for growth and flexibility; these structures contain thin seams called sutures that help the structure to absorb impacts. In this study, we parameterized the stiffness and toughness of a curved archway structure based on three geometric properties of a suture through finite element, quasi-static, three-point bending simulations. Each archway consisted of two symmetric pieces linked by a dovetail suture tab design. The three parameters included suture tab radii (1-5 mm), tangent lengths (0-20 mm), and contact angles (0-40°). In the simulations, a steel indenter was displaced 6.5 mm to induce progressive tab disengagement. Sutures with large contact angles and large tangent lengths generally led to stiffer and tougher structures. Sutures with a small tab radius exhibited the most sensitivity to the input parameters, and the smallest tab radius led to the stiffest and toughest archways. Results suggested that it was a combination of the largest number of tab repeats with the largest possible contact surface area that improved the mechanical response of the archway. The study revealed several suture geometries that hold significant promise, which can aid in the development of hemispherical 3D structures for dynamic impact applications.

Opioid sparing effect of ketamine in military prehospital pain management-A retrospective study.

BACKGROUND: Opioids are the most commonly used analgesics in acute trauma, but are limited by slow onset and significant adverse effects. Ketamine is an effective and widely used analgesic. This study was aimed to evaluate the effectiveness and opioid-sparing effects of ketamine when used in prehospital military trauma setting. METHODS: A retrospective analysis of a prehospital military trauma registry between 2014 and 2020. Inclusion criteria were 16 years or older, two or more documented pain assessments, at least one indicating severe pain, and administration of opioids and/or low-dose ketamine. Joint hypothesis testing was used to compare casualties who received opioids only to those who received ketamine on outcomes of pain score reduction and opioid consumption. RESULTS: Overall, 382 casualties were included. Ninety-one (24%) received ketamine (21 as a single analgesic), with a mean dose of 29 mg (standard deviation, 11). Mean reduction in pain scores (on an 11-point scale) was not significantly different; 4.3-point (2.8) reduction in the ketamine group and 3.7 points (2.4) in the opioid-only group ( p = 0.095). Casualties in the ketamine group received a median of 10 mg (interquartile range, 3.5-25) of morphine equivalents (MEs) compared with a median of 20 ME (10, 20) in the opioid-only group. In a multivariable multinomial logistic regression, casualties in the ketamine group were significantly more likely to receive a low (1-10 ME) rather than a medium (11-20 ME) dose of opioids compared with the opioid-only group (odds ratio, 0.032; 95% confidence interval, 0.14-0.75). CONCLUSION: The use of ketamine in the prehospital military setting as part of a pain management protocol was associated with a low rather than medium dose of opioids in a multivariable analysis, while the mean reduction in pain scores was not significantly different between groups. Using ketamine as a first-line agent may further reduce opioid consumption with a similar analgesic effect. LEVEL OF EVIDENCE: Therapeutic/care management; Level IV.

Wavefront shaping with a Hadamard basis for scattering soil imaging.

Soil is a scattering medium that inhibits imaging of plant-microbial-mineral interactions that are essential to plant health and soil carbon sequestration. However, optical imaging in the complex medium of soil has been stymied by the seemingly intractable problems of scattering and contrast. Here, we develop a wavefront shaping method based on adaptive stochastic parallel gradient descent optimization with a Hadamard basis to focus light through soil mineral samples. Our approach allows a sparse representation of the wavefront with reduced dimensionality for the optimization. We further divide the used Hadamard basis set into subsets and optimize a certain subset at once. Simulation and experimental optimization results demonstrate our method has an approximately seven times higher convergence rate and overall better performance compared to that with optimizing all pixels at once. The proposed method can benefit other high-dimensional optimization problems in adaptive optics and wavefront shaping.

Efficacy of hyoscine in pain management during hysteroscopy: a systematic review and meta-analysis

We conducted a systematic review and meta-analysis of relevant clinical trials from full-text, scientific journal archives to assess the efficacy of hyoscine for the management of pain during in-office hysteroscopy (OH) procedures. Cochrane CENTRAL, ClinicalTrials.Gov, MEDLINE, PubMed, SCOPUS and the Web of Science were searched for all clinical trials that matched our search criteria. A full assessment of bias was made using the Cochrane Group tool-set. The following outcomes were included: visual analogue scale (VAS) score for postoperative pain, postoperative need for analgesia, and procedure time. In the case of homogeneous data, the analysis was performed using a fixed effects system, and the random effects system was used with heterogeneous data. Inclusion criteria included only randomized clinical trials, and interventions that included patients receiving hyoscine-N-Butyl Bromide during OH, regardless of dose or mode of administration, and compared this with placebo. Three clinical trials were included. The actual mean difference (MD) of the VAS pain score showed no significant difference between hyoscine or placebo [MD: -0.28 (-1.08, 0.52), (p=0.49)]. For postoperative analgesia, the overall MD showed no significant difference between hyoscine or placebo [MD: 0.43 (0.16, 1.14), (p=0.09)]. For procedure time, the combined effect estimate failed to show any significant difference between hyoscine and placebo [MD: -0.66 (-2.77, 1.44) (p=0.54)]. Contrary to previously published data, our meta-analysis using the latest available RCTs fails to show hyoscine as being effective in reducing pain or the need for other forms of anesthesia in OH.

Characterization of the liver immune microenvironment in liver biopsies from patients with chronic HBV infection.

BACKGROUND & AIMS: We aim to describe the liver immune microenvironment by analyzing liver biopsies from patients with chronic HBV infection (CHB). Host immune cell signatures and their corresponding localization were characterized by analyzing the intrahepatic transcriptome in combination with a custom multiplex immunofluorescence panel. METHOD: Matching FFPE and fresh frozen liver biopsies were collected from immune active patients within the open-label phase IV study GS-US-174-0149. RNA-Seq was conducted on 53 CHB liver biopsies from 46 patients. Twenty-eight of the 53 samples had matched FFPE biopsies and were stained with a 12-plex panel including cell segmentation, immune and viral biomarkers. Corresponding serum samples were screened using the MSD Human V-plex Screen Service to identify peripheral correlates for the immune microenvironment. RESULTS: Using unsupervised clustering of the transcriptome, we reveal two unique liver immune signatures classified as immune high and immune low based on the quantification of the liver infiltrate gene signatures. Multiplex immunofluorescence analysis demonstrated large periportal lymphoid aggregates in immune high samples consisting of CD4 and CD8 T cells, B cells and macrophages. Differentiation of the high and low immune microenvironments was independent of HBeAg status and peripheral viral antigen levels. In addition, longitudinal analysis indicates that treatment and normalization of ALT correlates with a decrease in liver immune infiltrate and inflammation. Finally, we screened a panel of peripheral biomarkers and identified ICAM-1 and CXCL10 as biomarkers that strongly correlate with these unique immune microenvironments. CONCLUSION: These data provide a description of immune phenotypes in patients with CHB and show that immune responses are downregulated in the liver following nucleotide analogue treatment. This may have important implications for both the safety and efficacy of immune modulator programs aimed at HBV cure. LAY SUMMARY: Liver biopsies from patients with chronic hepatitis B were submitted to RNA-Seq and multiplex immunofluorescence and identified two different liver immune microenvironments: immune high and immune low. Immune high patients showed elevated immune pathways, including interferon signaling pathways, and increase presence of immune cells. Longitudinal analysis of biopsies from treatment experienced patients showed that treatment correlates with a marked decrease in inflammation and these findings may have important implications for both safety and efficacy of immune modulator programs for HBV cure.

Oral Selective TLR8 Agonist Selgantolimod Induces Multiple Immune Cell Responses in Humans.

TLR8 agonists have the potential for use as immunomodulatory components in therapeutic modalities for viral infections such as chronic HBV (CHB) and HIV. In this study, using peripheral blood samples from a phase 1a clinical trial, we examined the acute effects of a single oral administration of a selective TLR8 agonist on immune cell phenotypes. Administration of the TLR8 agonist selgantolimod (SLGN) in healthy individuals resulted in alteration in frequencies of peripheral blood monocytes, pDCs, mDCs and MAIT cells. Frequencies of mDCs and lymphoid cells significantly reduced after 8 h of SLGN administration, whereas pDC frequencies significantly increased, with changes possibly reflecting migration of different cell types between peripheral and tissue compartments in response to the agonist. Myeloid cell activation was evident by an upregulated expression of co-stimulatory molecules CD40 and CD86 accompanied by the production of IL-6 and IL-18 from these cells. Concomitantly, there was induction of the early activation marker CD69 on innate and adaptive lymphoid cells, including MAIT and NK cell subsets. Further, these activated lymphoid cells had enhanced expression of the effector molecules granzyme B and perforin. Microarray analysis of isolated lymphocytes and monocytes from baseline and post-SLGN treatment revealed changes in expression of genes involved in cellular response to cytokine stimulus, innate immune response, myeloid cell differentiation and antigen receptor-mediated signaling pathway. In a preliminary analysis of samples from CHB patients treated with selgantolimod, activation of innate and adaptive lymphocytes was evident. In conclusion, this first in-human study shows that selgantolimod administration in humans results in activation of multiple immune cell responses with antiviral potential.

ATS Core Curriculum 2021. Pediatric Pulmonary Medicine: Pulmonary Infections.

The following is a concise review of the Pediatric Pulmonary Medicine Core reviewing pediatric pulmonary infections, diagnostic assays, and imaging techniques presented at the 2021 American Thoracic Society Core Curriculum. Molecular methods have revolutionized microbiology. We highlight the need to collect appropriate samples for detection of specific pathogens or for panels and understand the limitations of the assays. Considerable progress has been made in imaging modalities for detecting pediatric pulmonary infections. Specifically, lung ultrasound and lung magnetic resonance imaging are promising radiation-free diagnostic tools, with results comparable with their radiation-exposing counterparts, for the evaluation and management of pulmonary infections. Clinicians caring for children with pulmonary disease should ensure that patients at risk for nontuberculous mycobacteria disease are identified and receive appropriate nontuberculous mycobacteria screening, monitoring, and treatment. Children with coronavirus disease (COVID-19) typically present with mild symptoms, but some may develop severe disease. Treatment is mainly supportive care, and most patients make a full recovery. Anticipatory guidance and appropriate counseling from pediatricians on social distancing and diagnostic testing remain vital to curbing the pandemic. The pediatric immunocompromised patient is at risk for invasive and opportunistic pulmonary infections. Prompt recognition of predisposing risk factors, combined with knowledge of clinical characteristics of microbial pathogens, can assist in the diagnosis and treatment of specific bacterial, viral, or fungal diseases.

A Systematic Review and Meta-Analysis of Intraperitoneal Bupivacaine in Laparoscopic Gynecologic Surgery.

OBJECTIVE: We set out to evaluate whether the instillation of bupivacaine versus a saline solution into the peritoneal cavity at time of laparoscopic gynecologic surgery will reduce postoperative pain and postoperative opioid consumption. DATA SOURCES: We searched six databases: Web of Science, SCOPUS, Cochrane CENTRAL, ClinicalTrials.Gov, MEDLINE and PubMed. Our search strategy had no restriction on time or languages and included all studies that met our search algorithm up to March of 2021. METHODS OF STUDY SELECTION: We included only randomized trials that met our search strategy for the outcomes of 1) pain intensity 24 hours after surgery, 2) pain intensity 6 hours after surgery, and 3) length of hospital stay. TABULATION INTEGRATION AND RESULTS: We analyzed continuous data using mean difference (MD) with relative 95% confidence interval (CI). We included 8 randomized clinical trials. We found that intraperitoneal bupivacaine showed significant difference from the saline group regarding pain intensity 24 hours after surgery (MD= -0.73 [-1.10, -0.36]) (P = 0.01) and pain intensity 6 hours after surgery (MD= -1.12 [-2.22, -0.02]) (P = 0.05). Overall, patients allocated to the placebo group seemed to need other analgesics earlier than patients allocated to the bupivacaine group (MD=145.08 [51.37, 238.79] (P = 0.02)). There was no significant difference regarding the length of hospital stay (MD= -0.44 [-1.44, 0.56]) (P = 0.39). CONCLUSION: Bupivacaine significantly reduced the visual analog pain score for pain compared with that of the placebo at 6 and 24 hours postoperatively. There was no significant difference in hospital stay. PROSPERO REGISTRATION: CRD42021254268.