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Ischemic stroke is a major disease causing death and disability in the elderly and is one of the major diseases that seriously threaten human health and cause a great economic burden. In the early stage of ischemic stroke, neuronal structure is destroyed, resulting in death or damage, and the release of a variety of damage-associated pattern molecules induces an increase in neuroglial activation, peripheral immune response, and secretion of inflammatory mediators, which further exacerbates the damage to the blood–brain barrier, exacerbates cerebral edema, and microcirculatory impairment, triggering secondary brain injuries. After the acute phase of stroke, various immune cells initiate a protective effect, which is released step by step and contributes to the repair of neuronal cells through phenotypic changes. In addition, ischemic stroke induces Central Nervous System (CNS) immunosuppression, and the interaction between the two influences the outcome of stroke. Therefore, modulating the immune response of the CNS to reduce the inflammatory response and immune damage during stroke is important for the protection of brain function and long-term recovery after stroke, and modulating the immune function of the CNS is expected to be a novel therapeutic strategy. However, there are fewer studies on B-cells in brain function protection, which may play a dual role in the stroke process, and the understanding of this cell is still incomplete. We review the existing studies on the mechanisms of the role of B-cells, inflammatory response, and immune response in the development of ischemic stroke and provide a reference for the development of adjuvant therapeutic drugs for ischemic stroke targeting inflammatory injury.

Introduction: The response to medical management of young dogs with osteoarthritis (OA) associated pain has not been evaluated. Using an open-label design, the effectiveness, over a 4-month period, of standardized management (grapiprant/fish oil/exercise) for treating OA pain in young dogs was evaluated., Methods: Included dogs were 9 months-4 years of age; ≥3.6 kg body weight; had ≥1 appendicular joint with radiographic OA and obvious joint pain; had a Liverpool Osteoarthritis in Dogs (LOAD) score of ≥5. The non-steroidal anti-inflammatory piprant (grapiprant) was given at the recommended dose daily, omega-3 fatty acid supplementation was initiated at 100 mg/kg and then increased to 200 mg/kg daily, and leash exercise was gradually increased to a target of 60 min daily. Client-reported outcome measures (CROMs) and force plate gait analysis were collected at baseline and monthly for 4 months. The index limb was defined as the most severely affected limb at baseline., Results: Forty-eight dogs were enrolled (mean ± SD age of 30.7 ± 10.7 months). Hips, elbows, and stifles were commonly affected. Medication and supplement compliance was excellent (≥95% of target administered), and treatments were well-tolerated. CROMs showed significant improvement over time and at each time point. Overall, peak vertical force (PVF) increased significantly (<0.001), and vertical impulse increased numerically. Increase in PVF from baseline was significant at all time points except 4-months., Discussion: This study demonstrates a clinically meaningful benefit of a multimodal treatment regimen over a 4-month period for young dogs (<4 years old) with OA-pain. Future work should determine if early, effective treatment is of long-term benefit., Competing Interests: The authors declare that this study received funding from Elanco Animal Health (NC State Grant # 2020-0044). The funder was not involved in the study design, collection, analysis, interpretation of data, or the decision to submit it for publication. However, the manuscript went through an internal review and approval process at Elanco Animal Health before submission to check for potential disclosure of confidential information. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Enomoto, Hash, Cole, Porcel Sanchez, Thomson, Perry, Aker, Nakanishi-Hester, Haupt, Opperman, Roe, Thompson, Innes and Lascelles.)

Background: The widespread use of pneumococcal conjugate vaccines (PCV) has changed the epidemiology of invasive pneumococcal disease (IPD) in children globally., Methods: Multicentre prospective audit of IPD episodes from five paediatric hospitals in Australia over 5.5 years between 2016 and June 2021. Children (<18 years) with Streptococcus pneumoniae isolated from a sterile site were included., Results: There were 377 IPD episodes in 375 children: 338 (90%) had received ≥3 PCV doses; 42 (11%) had IPD risk factors. The most common presentations were complicated pneumonia (254, 67%), bacteraemia (65, 17%) and meningitis (29, 8%). Five (1%) children died.Serotype information was available for 230 (61%) episodes; 140 (61%) were 13vPCV vaccine serotypes (VTs). The majority (85%) of episodes of complicated pneumonia were due to a VT; predominantly 3, 19A, 19F. Children with risk factors were more likely to present with bacteraemia ± sepsis (42% vs 12%) and to have a non-vaccine serotype (NVT) (74% vs 32%). Resistance to ceftriaxone (meningitis cut-off) occurred in 17% of 23B isolates (n=12) and accounted for 22% (5/23) of meningitis cases., Conclusions: Complicated pneumonia is the most common IPD presentation. NVTs account for the majority of bacteraemia and meningitis episodes. High rates of ceftriaxone resistance for NVT 23B support the addition of vancomycin for empiric treatment of suspected meningitis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Intravenous ganciclovir (GCV) is used for the treatment of cytomegalovirus (CMV) infection in immunocompromised children. Although the therapeutic target for treatment is unclear, studies have shown a serum area under the concentration-time curve (AUC 24h ) ≥40 mg/L·h correlates with effective CMV prevention. This study aimed to externally validate existing GCV population pharmacokinetic (PopPK) models and develop a model if needed and evaluate the serum AUC 24h achieved with standard GCV dosing and propose an optimized dosing strategy for immunocompromised children. Ganciclovir drug monitoring data from two pediatric hospitals were retrospectively collected, and published pediatric PopPK models were externally validated. The population AUC 24h with standard GCV dosing (5 mg/kg twice daily) was calculated, and an optimized dosing strategy was determined using Monte Carlo simulations to achieve an AUC 24h between 40 and 100 mg/L·h. Overall, 161 samples from 23 children with a median (range) age of 9.0 years (0.4-17.0) and weight of 28.2 kg (5.6-73.3) were analyzed. Transferability of published pediatric PopPK models was limited. Thus, a one-compartment model with first-order absorption and elimination with weight and serum creatinine as covariates was developed. The median (5th-95th percentiles) steady state AUC 24h with standard dosing was 38.3 mg/L·h (24.8-329.2) with 13 children having an AUC 24h <40 mg/L·h, particularly those aged <4 years (8/13). An optimized simulated GCV dosing regimen, ranging from 2 to 13 mg/kg twice daily for children with normal renal function, achieved 61%-78% probability of target attainment. Standard GCV dosing likely results in inadequate drug exposure in more than half of the children, particularly those aged <4 years. An optimized dosing regimen has been proposed for clinical validation., Competing Interests: The authors declare no conflict of interest.

Background & Aims: For children and adolescents undergoing hematopoietic stem cell transplant (HSCT), adequate protein and energy intake is essential to mitigate malnutrition risk. However, little is known about optimal requirements, including adequate dietary protein intake in this population. We conducted an international benchmarking survey and a scoping review to explore current practices in determining protein requirements (PR) and examine existing evidence for PR and dietary protein intake in pediatric HSCT., Methods: Twelve pediatric oncology centers were surveyed to elicit current practices in determining PR in pediatric HSCT. A scoping review then collected sources of evidence from six databases (MEDLINE, Embase, CINAHL, PubMed, Cochrane Library and Web of Science) and grey literature (Google Scholar)., Results: Survey data revealed variable practices in determining PR for pediatric HSCT patients. Four centers (44%) used the American Society for Parenteral and Enteral Nutrition (ASPEN) Nutrition Support in Pediatric Critically Ill Patient Guidelines 2009 and four (44%) used local guidelines or their national nutrient reference values (NRV). The scoping review included nineteen studies. The review highlighted a broad range of PR used in this population, ranging from 0.8 to 3.0 g/kg/d. Practices regarding the documentation and frequency of collecting protein intake data varied. Only five studies reported estimated protein requirement (EPR) status and just two studies met EPR. No clinical guidelines on PR in pediatric HSCT were identified., Conclusions: Given the existing gap in evidence, the optimal amount of protein required for children and adolescents undergoing HSCT remains unknown. To establish specific, evidence-based PR guidelines, comprehensive research is needed. Future investigations should prioritize evaluating current clinical practices, assessing the gap between actual protein intake and EPR, and understanding the relationship between protein intake, protein status, and the impact on treatment outcomes. Addressing these research priorities is crucial for bridging the current evidence gap, thereby enabling the development of enhanced and personalized nutritional support for children and adolescents undergoing HSCT., Competing Interests: Declaration of competing interest There are no conflicts of interest to this study., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Objectives: Haematopoietic cell transplant (HCT) is a cellular therapy for a group of high-risk children with cancer, immunodeficiency and metabolic disorders. Whilst curative for a child's underlying condition, HCT has significant risks associated, including lung injury. These complications are associated with increased post HCT mortality and require improved methods of risk stratification, diagnosis and treatment., Methods: Biomarkers measured in bronchoalveolar fluid and peripheral blood have been identified for both acute and chronic lung injury post HCT.This review evaluates the current research available investigating the use of these biomarkers to improve clinical care, with a focus on the paediatric cohort., Results: Elevated levels of cytokines such as IL-6, IL-8, G-CSF and TNF were identified as potential predictive biomarkers for the development of post HCT lung disease. The pulmonary microbiome was found to have strong potential as a biomarker pre and post HCT for the development of pulmonary complications. General limitations of the studies identified were study design, retrospective or single centre and not exclusively performed in the paediatric population., Conclusion: To translate biomarker discovery into clinical implementation further research is required, utilising larger cohorts of children in prospective trials to validate these biomarkers and determine how they can be translated into better outcomes for children post HCT., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Objectives: Haematopoietic stem cell transplant (HCT) is a cellular therapy that, whilst curative for a child's underlying disease, carries significant risk of mortality, including because of pulmonary complications. The aims of this study were to describe the burden of pulmonary complications post-HCT in a cohort of Australian children and identify risk factors for the development of these complications., Methods: Patients were identified from the HCT databases at two paediatric transplant centres in Australia. Medical records were reviewed, and demographics, HCT characteristics and pulmonary complications documented. Relative risk ratio was used to identify risk factors for developing pulmonary complications prior to first transplant episode, and survival analysis performed to determine hazard ratio., Results: In total, 243 children underwent transplant during the study period, and pulmonary complications occurred in 48% (117/243) of children. Infectious complications were more common (55%) than non-infective complications (18%) and 26% of patients developed both. Risk factors for the development of pulmonary complications included the following: diagnoses of MPAL (RR 2.16, P  = 0.02), matched unrelated donor (RR1.34, P  = 0.03), peripheral blood (RR 1.36, P  = 0.028) or cord blood (RR 1.73, P  = 0.012) as the stem cell source and pre-existing lung disease (RR1.72, P  < 0.0001). Children with a post-HCT lung complication had a significantly increased risk of mortality compared with those who did not (HR 3.9, P  < 0.0001)., Conclusion: This study demonstrates pulmonary complications continue to occur frequently in children post-HCT and contribute significantly to mortality. Highlighting the need for improved strategies to identify patients at risk pre-transplant and enhanced treatments for those who develop lung disease., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Abstract: HLA-mismatched transplants with either in vitro depletion of CD3+ T-cell receptor (TCR)αβ/CD19 (TCRαβ) cells or in vivo T-cell depletion using posttransplant cyclophosphamide (PTCY) have been increasingly used for patients with inborn errors of immunity (IEIs). We performed a retrospective multicenter study via the EBMT registry on 306 children with IEIs undergoing their first transplant between 2010 and 2019 from an HLA-mismatched donor using TCRαβ (n = 167) or PTCY (n = 139). The median age for hematopoietic stem cell transplantation (HSCT) was 1.2 years (range, 0.03-19.6 years). The 3-year overall survival (OS) was 78% (95% confidence interval (CI), 71-84) after TCRαβ and 66% (57-74) after PTCY (P = .013). Pre-HSCT morbidity score (hazard ratio [HR], 2.27; 1.07-4.80, P = .032) and non-busulfan/treosulfan conditioning (HR, 3.12; 1.98-4.92, P < .001) were the only independent predictors of unfavorable OS. The 3-year event-free survival (EFS) was 58% (50%-66%) after TCRαβ and 57% (48%-66%) after PTCY (P = .804). The cumulative incidence of severe acute graft-versus-host disease (GvHD) was higher after PTCY (15%, 9%-21%) than TCRαβ (6%, 2%-9%, P = .007), with no difference in chronic GvHD (PTCY, 11%, 6%-17%; TCRαβ, 7%, 3%-11%, P = .173). The 3-year GvHD-free EFS was 53% (44%-61%) after TCRαβ and 41% (32%-50%) after PTCY (P = .080). PTCY had significantly higher rates of veno-occlusive disease (14.4% vs TCRαβ 4.9%, P = .009), acute kidney injury (12.7% vs 4.6%, P = .032), and pulmonary complications (38.2% vs 24.1%, P = .017). Adenoviremia (18.3% vs PTCY 8.0%, P = .015), primary graft failure (10% vs 5%, P = .048), and second HSCT (17.4% vs 7.9%, P = .023) were significantly higher in TCRαβ. In conclusion, this study demonstrates that both approaches are suitable options in patients with IEIs, although they are characterized by different advantages and outcomes., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: There is no vaccine against the major global pathogen Chlamydia trachomatis; its different serovars cause trachoma in the eye or chlamydia in the genital tract. We did a clinical trial administering CTH522, a recombinant version of the C trachomatis major outer membrane molecule, in different dose concentrations with and without adjuvant, to establish its safety and immunogenicity when administered intramuscularly, intradermally, and topically into the eye, in prime-boost regimens., Methods: CHLM-02 was a phase 1, double-blind, randomised, placebo-controlled trial at the National Institute for Health Research Imperial Clinical Research Facility, London, UK. Participants were healthy men and non-pregnant women aged 18-45 years, without pre-existing C trachomatis genital infection. Participants were assigned into six groups by the electronic database in a pre-prepared randomisation list (A-F). Participants were randomly assigned (1:1:1:1:1) to each of the groups A-E (12 participants each) and 6 were randomly assigned to group F. Investigators were masked to treatment allocation. Groups A-E received investigational medicinal product and group F received placebo only. Two liposomal adjuvants were compared, CAF01 and CAF09b. The groups were intramuscular 85 μg CTH522-CAF01, or placebo on day 0 and two boosters or placebo at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (A); intramuscular 85 μg CTH522-CAF01, two boosters at day 28 and 112 with additional topical ocular administration of CTH522, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (B); intramuscular 85 μg CTH522-CAF01, two boosters at day 28 and 112 with additional intradermal administration of CTH522, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (C); intramuscular 15 μg CTH522-CAF01, two boosters at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (D); intramuscular 85 μg CTH522-CAF09b, two boosters at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (E); intramuscular placebo (F). The primary outcome was safety; the secondary outcome (humoral immunogenicity) was the percentage of trial participants achieving anti-CTH522 IgG seroconversion, defined as four-fold and ten-fold increase over baseline concentrations. Analyses were done as intention to treat and as per protocol. The trial is registered with ClinicalTrials.gov, NCT03926728, and is complete., Findings: Between Feb 17, 2020 and Feb 22, 2022, of 154 participants screened, 65 were randomly assigned, and 60 completed the trial (34 [52%] of 65 women, 46 [71%] of 65 White, mean age 26·8 years). No serious adverse events occurred but one participant in group A2 discontinued dosing after having self-limiting adverse events after both placebo and investigational medicinal product doses. Study procedures were otherwise well tolerated; the majority of adverse events were mild to moderate, with only seven (1%) of 865 reported as grade 3 (severe). There was 100% four-fold seroconversion rate by day 42 in the active groups (A-E) and no seroconversion in the placebo group. Serum IgG anti-CTH522 titres were higher after 85 μg CTH522-CAF01 than 15 μg, although not significantly (intention-to-treat median IgG titre ratio groups A-C:D=5·6; p=0·062), with no difference after three injections of 85 μg CTH522-CAF01 compared with CTH522-CAF09b (group E). Intradermal CTH522 (group C) induced high titres of serum IgG anti-CTH522 neutralising antibodies against serovars B (trachoma) and D (urogenital). Topical ocular CTH522 (group B) at day 28 and 112 induced higher total ocular IgA compared with baseline (p<0·001). Participants in all active vaccine groups, particularly groups B and E, developed cell mediated immune responses against CTH522., Interpretation: CTH522, adjuvanted with CAF01 or CAF09b, is safe and immunogenic, with 85 μg CTH522-CAF01 inducing robust serum IgG binding titres. Intradermal vaccination conferred systemic IgG neutralisation breadth, and topical ocular administration increased ocular IgA formation. These findings indicate CTH522 vaccine regimens against ocular trachoma and urogenital chlamydia for testing in phase 2, clinical trials., Funding: The EU Horizon Program TRACVAC., Competing Interests: Declaration of interests KMP had membership of the data safety monitoring board for NCT05249829 and has membership for NCT05575492, has received a fee for speaking from Seqirus and Sanofi Pasteur, and has research funding from the Chan Zuckerberg Initiative, the Medical Research Council–UK Research and Innovation, the Vaccine Task Force, and National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC) outside the submitted work. PLA, FF, IR, and AWO are co-inventors on a patent for vaccines against chlamydia [US10925954, EP2976355]. All rights have been assigned to Statens Serum Institut, a Danish not-for-profit institute under the Ministry of Health. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the participant matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objectives: Posaconazole is increasingly used for the treatment and prophylaxis of invasive fungal infections in immunocompromised children. We aimed to review evidence for paediatric posaconazole dosing regimens focusing on attainment of target concentrations and frequency of adverse effects., Methods: In May 2023, the Cochrane, Embase, MEDLINE and PubMed databases were searched for articles reporting posaconazole dosing in children with malignancy or post-haematopoietic stem cell transplantation. Studies reporting the attainment of target serum concentrations were included., Results: Overall, 24 studies were included. Eighteen studies of the oral suspension consistently reported poor attainment of target concentrations for prophylaxis (≥0.7 µg/mL, 12%-78%) despite high daily doses of 14-23 mg/kg/day (max. 1200 mg/day). Target attainment was significantly affected by gastric pH and food intake. Six studies of the delayed-release tablet (DRT) reported 58%-94% achieved concentrations ≥0.7 µg/mL, with the majority using lower doses of 4-12 mg/kg/day (max. 300 mg/day). Similarly, one study of powder for oral suspension found 67%-100% achieved target concentrations with a dose of 6 mg/kg/day (max. 300 mg/day). As expected, the IV formulation had high attainment of prophylaxis targets (81%-90%) with 6-10 mg/kg/day (max. 400 mg/day). All formulations were well tolerated, and no relationship between adverse effects and posaconazole concentrations was identified., Conclusions: The required posaconazole dose in immunocompromised children varies depending on the formulation. The IV infusion had the highest attainment of therapeutic concentration followed by the DRT and powder for suspension. By contrast, the oral suspension had low attainment of target concentrations despite higher daily doses., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Abstract: Wiskott-Aldrich syndrome (WAS) is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (range, 0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% confidence interval, 78-87) at age 15 years and 70% (61-80) at 30 years. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hot spot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared with 71% (62-81) and 48% (34-68) in patients with any other variant (class II; P < .0001). The cumulative incidence rates of disease-related complications such as severe bleeding (P = .007), life-threatening infection (P < .0001), and autoimmunity (P = .004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (P = .6) was not different between classes I and II. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of the variant is a biomarker to predict the outcome for patients with WAS.

Repetitive overhead tasks during factory work can cause shoulder injuries resulting in impaired health and productivity loss. Soft wearable upper extremity robots have the potential to be effective injury prevention tools with minimal restrictions using soft materials and active controls. We present the design and evaluation of a portable inflatable shoulder wearable robot for assisting industrial workers during shoulder-elevated tasks. The robot is worn like a shirt with integrated textile pneumatic actuators, inertial measurement units, and a portable actuation unit. It can provide up to 6.6 newton-meters of torque to support the shoulder and cycle assistance on and off at six times per minute. From human participant evaluations during simulated industrial tasks, the robot reduced agonist muscle activities (anterior, middle, and posterior deltoids and biceps brachii) by up to 40% with slight changes in joint angles of less than 7% range of motion while not increasing antagonistic muscle activity (latissimus dorsi) in current sample size. Comparison of controller parameters further highlighted that higher assistance magnitude and earlier assistance timing resulted in statistically significant muscle activity reductions. During a task circuit with dynamic transitions among the tasks, the kinematics-based controller of the robot showed robustness to misinflations (96% true negative rate and 91% true positive rate), indicating minimal disturbances to the user when assistance was not required. A preliminary evaluation of a pressure modulation profile also highlighted a trade-off between user perception and hardware demands. Finally, five automotive factory workers used the robot in a pilot manufacturing area and provided feedback.

Study Design: Systematic review., Background: Proximal phalangeal fractures of the hand are challenging to treat, and significantly impact hand function and quality of life if poorly managed., Purpose: A systematic review to determine the efficacy of conservatively managed extra-articular proximal phalanx fractures to optimise recovery and prevent the need for surgical intervention and its associated risks., Methods: A literature search that included variations of the phrases 'proximal phalanx', 'fracture' and 'conservative management' was performed on 17 December 2023 using seven electronic databases and trial registries. Article screening, data extraction and critical appraisal using the Structured Effectiveness Quality Evaluation scale was performed independently., Results: Seven studies that captured 389 fractures from 356 unique patients were included. Studies were of level II to IV evidence and included one comparative cohort study and six prospective case series. Interventions involved timely rehabilitation, a plaster or orthotic device, controlled metacarpophalangeal joint flexion and free mobilisation of the interphalangeal joints. A weighted mean total active motion score of 249° was achieved, with 99.5% (387/389) of fractures achieving union., Conclusions: This systematic review cautions against definitive recommendations on conservative techniques for managing proximal phalanx fractures due to limitations of the available literature. However, our findings tentatively supports non-operative approaches as an alternative to surgery., Competing Interests: All authors declare no financial and personal conflicts of interest., (© 2024 The Authors. Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons.)

Bronchiolitis obliterans syndrome (BOS) is a severe complication following hemopoietic stem cell transplantation (HSCT) and is often undetected until there is significant deterioration in pulmonary function. Lung clearance index (LCI 2.5 ) derived from the nitrogen multiple breath washout (N 2 MBW) test may be more feasible and sensitive than spirometry, which is currently used for surveillance and detection of BOS. We aimed to examine the feasibility of performing surveillance N 2 MBW in children post-HSCT, and in an exploratory analysis, determine if LCI 2.5 led to earlier detection of BOS when compared to spirometric indices. Participants aged 5 to 17 years were recruited prior to receiving HSCT into a prospective, single-center, feasibility study at the Royal Children's Hospital, Melbourne. N 2 MBW and spirometry were performed within the month prior to transplant and repeated at 3, 6, 9, and 12 months post-transplant. Data were also collected on the presence of graft-versus-host (GVHD) disease in any organ, including the lungs. Twenty-one (12 male) children with a mean age of 13.4 (range 9.2 to 17.1) years at recruitment participated in this study. Prior to HSCT, all participants had normal LCI 2.5 , while 16 (76%) demonstrated normal forced expiratory volume in 1 second (FEV 1 ). Ninety-nine percent of N 2 MBW tests were technically acceptable, compared with 66% of spirometry tests. Three participants developed BOS, while 2 participants died of other respiratory complications. At 6 and 12 months post-transplant, the BOS group had increases in LCI 2.5 ranging from 3 to 5 units and mean reductions in FEV 1 % predicted of 40% to 53% relative to pre HSCT values, respectively. In those who developed BOS, post-HSCT LCI 2.5 values were significantly worse when compared with the no BOS group (P < .001). Relative changes in LCI 2.5 and FEV 1 were both predictive of BOS at 6 months post HSCT. This study demonstrates that N 2 MBW is a more feasible test compared with spirometry in children post HSCT. However, in an exploratory analysis, LCI 2.5 did not lead to earlier detection of BOS, when compared to spirometry., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The identification of somatic RB1 variation is crucial to confirm the heritability of retinoblastoma. We and others have previously shown that, when tumour DNA is unavailable, cell-free DNA (cfDNA) derived from aqueous humour (AH) can be used to identify somatic RB1 pathogenic variation. Here we report RB1 pathogenic variant detection, as well as cfDNA concentration in an extended cohort of 75 AH samples from 68 patients. We show cfDNA concentration is highly variable and significantly correlated with the collection point of the AH. Cell-free DNA concentrations above 5 pg/µL enabled the detection of 93% of known or expected RB1 pathogenic variants. In AH samples collected during intravitreal chemotherapy treatment (Tx), the yield of cfDNA above 5 pg/µL and subsequent variant detection was low (≤46%). However, AH collected by an anterior chamber tap after one to three cycles of primary chemotherapy (Dx1+) enabled the detection of 75% of expected pathogenic variants. Further limiting our analysis to Dx1+ samples taken after ≤2 cycles (Dx ≤ 2) provided measurable levels of cfDNA in all cases, and a subsequent variant detection rate of 95%. Early AH sampling is therefore likely to be important in maximising cfDNA concentration and the subsequent detection of somatic RB1 pathogenic variants in retinoblastoma patients undergoing conservative treatment.

Polyriboinosinic acid-polyribocytidylic acid (Poly I:C) serves as a synthetic mimic of viral double-stranded dsRNA, capable of inducing apoptosis in numerous cancer cells. Despite its potential, therapeutic benefits, the application of Poly I:C has been hindered by concerns regarding toxicity, stability, enzymatic degradation, and undue immune stimulation, leading to autoimmune disorders. To address these challenges, encapsulation of antitumor drugs within delivery systems such as cationic liposomes is often employed to enhance their efficacy while minimizing dosages. In this study, we investigated the potential of cationic liposomes to deliver Poly I:C into the Head and Neck 12 (HN12) cell line to induce apoptosis in the carcinoma cells and tumor model. Cationic liposomes made by the hydrodynamic focusing method surpass traditional methods by offering a continuous flow-based approach for encapsulating genes, which is ideal for efficient tumor delivery. DOTAP liposomes efficiently bind Poly I:C, confirmed by transmission electron microscopy images displaying their spherical morphology. Liposomes are easily endocytosed in HN12 cells, suggesting their potential for therapeutic gene and drug delivery in head and neck squamous carcinoma cells. Activation of apoptotic pathways involving MDA5, RIG-I, and TLR3 is evidenced by upregulated caspase-3, caspase-8, and IRF3 genes upon endocytosis of Poly(I:C)-encapsulated liposomes. Therapeutic evaluations revealed significant inhibition of tumor growth with Poly I:C liposomes, indicating the possibility of MDA5, RIG-I, and TLR3-induced apoptosis pathways via Poly I:C liposomes in HN12 xenografts in J:NU mouse models. Comparative histological analysis underscores enhanced cell death with Poly I:C liposomes, warranting further investigation into the precise mechanisms of apoptosis and inflammatory cytokine response in murine models for future research., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

This study aimed to determine the prevalence of osteoarthritis (OA) and associated clinical signs in young dogs. Owners of dogs aged 8 months-4 years from a single practice, were contacted in random order, to participate in a general health screen. Clinical and orthopedic examinations were performed. Each joint was scored for pain reactions (0-4). Orthogonal radiographs of all joints were made under sedation. Each joint was scored for radiographic OA (rOA) severity on an 11-point scale. Clinical OA (cOA) was defined as an overlap of rOA and joint pain in ≥ 1 joint. Owners completed OA questionnaires. The owners of 123 dogs agreed to participate. Overall, 39.8% (49/123) of dogs had rOA in ≥ 1 joint, and 16.3% (20/123) or 23.6% (29/123) dogs had cOA, depending on the cut-off value of joint pain; moderate (2), or mild (1), respectively. Owners of dogs with cOA observed signs of impairment in approximately 30% of cases. Only 2 dogs with cOA were receiving OA pain management. The most commonly affected joints in descending order of frequency were elbow, hip, tarsus, and stifle. Radiographically visible OA is common in young dogs, and 40-60% of dogs with rOA had cOA. However, OA-pain appears underdiagnosed and undertreated in young dogs., (© 2024. The Author(s).)

Hypochondroplasia (HCH) is a rare skeletal dysplasia causing mild short stature. There is a paucity of growth reference charts for this population. Anthropometric data were collected to generate height, weight, and head circumference (HC) growth reference charts for children with a diagnosis of HCH. Mixed longitudinal anthropometric data and genetic analysis results were collected from 14 European specialized skeletal dysplasia centers. Growth charts were generated using Generalized Additive Models for Location, Scale, and Shape. Measurements for height (983), weight (896), and HC (389) were collected from 188 (79 female) children with a diagnosis of HCH aged 0-18 years. Of the 84 children who underwent genetic testing, a pathogenic variant in FGFR3 was identified in 92% (77). The data were used to generate growth references for height, weight, and HC, plotted as charts with seven centiles from 2nd to 98th, for ages 0-4 and 0-16 years. HCH-specific growth charts are important in the clinical care of these children. They help to identify if other comorbidities are present that affect growth and development and serve as an important benchmark for any prospective interventional research studies and trials., (© 2023 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Telerehabilitation and robotics, either traditional rigid or soft, have been extensively studied and used to improve hand functionality after a stroke. However, a limited number of devices combined these two technologies to such a level of maturity that was possible to use them at the patients' home, unsupervised. Here we present a novel investigation that demonstrates the feasibility of a system that integrates a soft inflatable robotic glove, a cloud-connected software interface, and a telerehabilitation therapy. Ten chronic moderate-to-severe stroke survivors independently used the system at their home for 4 weeks, following a software-led therapy and being in touch with occupational therapists. Data from the therapy, including automatic assessments by the robot, were available to the occupational therapists in real-time, thanks to the cloud-connected capability of the system. The participants used the system intensively (about five times more movements per session than the standard care) for a total of more than 8 hr of therapy on average. We were able to observe improvements in standard clinical metrics (FMA +3.9 ± 4.0, p  < .05, COPM-P + 2.5 ± 1.3, p  < .05, COPM-S + 2.6 ± 1.9, p  < .05, MAL-AOU +6.6 ± 6.5, p  < .05) and range of motion (+88%) at the end of the intervention. Despite being small, these improvements sustained at follow-up, 2 weeks after the end of the therapy. These promising results pave the way toward further investigation for the deployment of combined soft robotic/telerehabilitive systems at-home for autonomous usage for stroke rehabilitation., Competing Interests: C.W. is the inventor of at least one patent application describing the inflatable soft robotic components described in the article that have been filed with the U.S. Patent Office by Harvard University. C.G., K.N., and C.W. co-founded Imago Rehab which has licensed the existing patents for soft robotic components from Harvard University. Imago Rehab did not fund the study. During study design and data collection, K.N. was not yet employed by Imago Rehab. C.G. discontinued all work on the study and employment at Harvard University at the conception of Imago Rehab. The remaining authors declare none., (© The Author(s) 2024.)

Microalgae not only play a vital role in the ecosystem but also hold promising commercial applications. Conventional methods of detecting and monitoring microalgae rely on field sampling followed by transportation to the laboratory for manual analysis, which is both time-consuming and laborious. Although machine learning (ML) algorithms have been introduced for microalgae detection in the laboratory, no integrated platform approach has yet emerged to enable real-time, on-site sampling and analysing. To solve this problem, here, we develop an automated and intelligent microfluidic platform (AIMP) that can offer automated system control, intelligent data analysis, and user interaction, providing an economical and portable solution to alleviate the drawbacks of conventional methods for microalgae detection and monitoring. We demonstrate the feasibility of the AIMP by detecting and classifying four microalgal species ( Cosmarium , Closterium , Micrasterias , and Haematococcus Pluvialis ) that exhibit varying sizes (from a few to hundreds of microns) and morphologies. The trained microalgae species detection network (MSDN, based on YOLOv5 architecture) achieves a high overall mean average precision at 0.5 intersection-over-union (mAP@0.5) of 92.8%. Furthermore, the versatility of the AIMP is demonstrated by long-term monitoring of astaxanthin production from Haematococcus Pluvialis over a period of 30 days. The AIMP achieved 97.5% accuracy in the detection of Haematococcus Pluvialis and 96.3% in further classification based on astaxanthin accumulation. This study opens up a new path towards microalgae detection and monitoring using portable intelligent devices, providing new ideas to accelerate progress in the ecological studies and commercial exploitation of microalgae.

Background: Valid measurement of drug use in patients enrolled in clinical trials that treat substance use disorder is vital to determine the trial's outcome. Self-reports are often used but their validity has been studied with mixed results. Urinalysis may sometimes be employed as an alternative or supplement to self-reports. Objectives: This study examined how estimating drug use by either method would affect the results from a randomized clinical trial conducted in a methadone treatment program. At the initial Baseline interview and four follow-up interviews, participants were asked about their drug use history and provided a urine specimen for drug testing. Results: In most cases, the urinalyses detected more drugs than the patients had reported using. A major exception was heroin, whose use was an eligibility criterion for enrollment in the study and methadone treatment. Conclusions: The patients' self-reports would have led us to conclude that the use of heroin and fentanyl had declined from the initial Baseline interview to the final follow-up interview, while the urinalysis results indicated no change in exposure to heroin and an increase in exposure to fentanyl. Clinical trials would be well served to employ the use of biological tests in addition to self-reports to measure recent drug use and to accurately estimate the efficacy of the experimental protocols and patients' exposure to drugs.