Laboratory cultivation subjects model organisms to selective pressure and genetic drift that can result in the accumulation of many genomic and phenotypic differences over time. The nematode Caenorhabditis elegans has been used for research since the 1970s, and studies comparing the N2 Bristol and CB4856 Hawaiian isolates provided foundational knowledge about metazoan genome evolution. Most comparative genomics studies have used these isolates because their long-term geographical isolation promoted a high degree of genomic divergence within the species. Further, there is growing evidence of phenotypic differences between laboratory lineages of each wild type isolate after repeated independent lab cultivation of these strains. To examine the genomic divergence between different laboratory lineages the Bristol and Hawaiian backgrounds, we first generated de novo genome assemblies of two Bristol and two Hawaiian lineages from Illumina and PacBio sequencing reads. Following genome assembly, we quantified Single Nucleotide Polymorphisms (SNPs), short insertion/deletions (indels), and genomic structural variants (SVs). Between laboratory lineages of the Bristol isolate, we identified 25,432 SNPs, 5,202 indels, and 441 SVs. When aligning laboratory lineages of the Hawaiian isolate, we identified 4,518 SNPs, 1,188 indels, and 387 SVs. For both sets of comparisons, we find that SNPs and indels are broadly enriched in introns and depleted from coding sequences. In contrast to SNPs and indels, we find that genomic SVs are enriched in intergenic sequences. Taken together, our analyses reveal the accumulation of genomic divergence between lineages of Bristol and Hawaiian C. elegans from independent lab cultivation, and how these variants may underpin emergent phenotypic differences observed in the two most popularly used C. elegans wild type isolates. Laboratory model organisms, like natural populations, are subject to evolutionary pressures and genomic changes during prolonged laboratory cultivation. In this study we comprehensively quantify SNPs, indels, and SVs between independent lab cultivations of the C. elegans lineages of the Bristol and Hawaiian isolates.
Results from the MORPHEUS-Lung (NCT03337698) study suggest that atezolizumab + bevacizumab + stereotactic body radiotherapy (SBRT) was associated with numerically improved efficacy outcomes vs docetaxel (control) in immune checkpoint inhibitor-exposed patients with metastatic non-small cell lung cancer. We report exploratory analyses to identify potential biomarkers associated with this clinical response. Tumor samples were analyzed for differential gene expression and pathway/immune subset gene signatures by single cell RNA-sequencing and further validated with bulk RNA-sequencing. The biomarker-evaluable population included 58 patients from two cohorts (atezolizumab + bevacizumab + SBRT, n = 26; docetaxel [control], n = 32). In a discovery study, analyses of clinical benefit (CB) vs non-CB groups at baseline showed that resident-memory CD8 T cells (TRM) were significantly enriched (P = 0.027; Gini index: P = 0.018), and expression of CXCL10+ and FOLR2+ macrophages was increased in the CB group. Pre- and post-treatment analysis showed that expression of effector-memory CD45RA+ CD8 T cells(TEMRA), CD8 TRM, and FOLR2+ and FABP4+ macrophages were numerically increased post-treatment. Together these results led to the identification of curated T-cell- and macrophage-associated gene response signatures. Using a confirmatory cohort, gene signature expression aligned with survival outcomes for patients receiving atezolizumab + bevacizumab + SBRT. These results suggest that activation of T cells and macrophages are associated with a favorable clinical response to atezolizumab + bevacizumab + SBRT. Moreover, CD8 TRM, CD8 exhausted T cells, and CXCL10+ macrophages may serve as potential biomarkers of response to atezolizumab + bevacizumab + SBRT treatment and potentially aid in tailored, precision medicine for individual patients.
Men with obesity infrequently engage with weight management services. To determine: (1) percentage weight loss at 12 and 24 months for text messages with or without financial incentives compared to control; (2) secondary outcomes; (3) cost-effectiveness; (4) moderators of effectiveness and (5) participant and stakeholder perspectives. Assessor-blinded randomised controlled trial. United Kingdom National Health Service perspective cost-effectiveness over 24 months and modelled lifetime horizon. Mixed-methods process evaluation. Five hundred and eighty-five men with body mass index ≥ 30 kg/m2 enrolled (July 2021-May 2022) in Belfast, Bristol and Glasgow; final follow-up June 2024. Random allocation to 12 months of behavioural text messages plus financial incentives (N = 196), same texts alone (N = 194) or 12-month waiting list control group offered 3 months of texts between 12 and 15 months (N = 195). A £400 financial incentive was lost if weight loss targets were not met. Weight change as a percentage of baseline weight at 12 and 24 months comparing control with (1) texts with financial incentives and (2) texts alone. Of 585 men (mean age 51 years; mean weight: 119 kg), 227 (39%) lived in lower socioeconomic areas, 146 (25%) reported a mental health condition and 253 (40%) had multiple long-term conditions. Follow-up was completed by 426 (73%) at 12 months and 377 (64%) at 24 months. At 12 months, mean percentage weight changes (standard deviation) were -4.8% (6.1) (-5.7 kg), -2.7% (6.3) (-3.0 kg), and - 1.3% (5.5) (-1.5 kg) for the incentives, text-only, and control groups, respectively. Compared to control, weight loss was significantly greater with incentives [-3.2% (97.5% confidence interval -4.6 to -1.9; p < 0.001)] but not texts alone (-1.4%; confidence interval -2.9 to 0.0; p = 0.053). At 24 months, changes were -3.9% (-4.6 kg), -2.6% (-3.1 kg), and -2.2% (-2.6 kg), no significant between-group differences. Intervention costs were £243 for texts with incentives, £110 for texts alone. There were no significant differences between 24-month costs and quality-adjusted life-years. Long-term modelling found texts with incentives versus control were: quality-adjusted life-year difference (95% confidence interval): 0.02 (0.007 to 0.029); cost difference: £176 (£43; £311); incremental cost-effectiveness ratio: £9748 (£7705 to £11,791). For texts alone versus control: quality-adjusted life-year difference: 0.03 (0.015 to 0.037); cost difference: £16.5 (-£117; £152); incremental cost-effectiveness ratio: £628 (-£5914 to £5384). There were no moderator effects for socioeconomic, health or well-being status for either comparison versus control. The texts with incentives group had a higher engagement in weight goal setting, food changes, self-weighing, confidence, satisfaction and quality of life compared to the control. Generalisability to women, diverse ethnic groups and people with low literacy is uncertain. Not generalisable to people with no mobile phone access. Retention was lowest in the text messages alone group. Texts with financial incentives have a modest but important effect to 12 months with clinically relevant weight loss maintenance to 24 months, are cost-effective and equally effective regardless of socioeconomic or health characteristics. Implementation, adapt for women, other cultures and longer-term follow-up. This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme as award number NIHR129703. The Game of Stones study aimed to help men lose weight and keep it off for at least 2 years. Five hundred and eighty-five men living with obesity across the United Kingdom were split into three groups by chance: supportive text messages for 1 year and opportunity to get money for weight loss the same text messages alone for 1 year neither for 1 year, then text messages for 3 months. The first two groups received the same daily text messages about changing weight-related behaviours. Group 1 was told at the start that £400 had been put aside for them and that money would be lost if weight targets were missed. The targets were 5% weight loss at 3 months, 10% at 6 months and maintaining that 10% loss at 12 months. Money was then paid to the men after being weighed at 12 months. Every man was asked questions about their health, well-being and experiences of being in the study. After 1 year, the men in group 1 lost the most weight (5%, 5.7 kg). The men in group 2 lost some weight (3%, 3.0 kg) but not as much as the first group. The men in group 3 lost the smallest amount of weight (1%, 1.5 kg). On average, men in group 1 received £128 for meeting weight loss targets. One year after the 12-month measures, men in groups 1 and 2 had gained back some weight. Men in group 3 lost a bit more weight between year 1 and 2. Weight loss was similar whether or not men had long-term health conditions, disability, mental health issues or lived in the most deprived areas. This study showed that Game of Stones was a popular, low-cost and modestly effective way of helping men to lose weight.
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Visual impairments (VI) affect over 2.2 billion people worldwide and are linked to an increased risk of falls. To date, no reviews have systematically synthesised evidence for the effect of VI on whole body gait biomechanics, to better understand how different types of VI might affect gait. A systematic search up to July 2025 was conducted using PubMed (MEDLINE), Scopus, Web of Science, and ERIC. Eligible studies included adults, a diagnosed or simulated VI, a non-visually impaired comparator, and reported any of the following gait parameters: 1) Spatio-temporal; 2) Kinetics; 3) Kinematics; and 4) Muscle activity. Study quality was evaluated using quality assessment with diverse studies (QuADS) and a narrative synthesis undertaken (SWiM). Forty-four studies were included. Twenty-seven examined straight-line level walking, 12 examined obstacle walking and five examined both straight-line level and obstacle walking. Of those examining straight-line level walking, 12 simulated VI and 15 explored diagnosed VI's. In the obstacle walking literature, nine simulated VI and six included participants with diagnosed VI's. Inconsistent findings were common across studies, with most reporting either a more cautious gait strategy with VI, or no difference between VI and non-VI conditions. Differences between studies are likely explained by variation in gait measurement, non-standard VI simulation methods, and lack of detail surrounding the severity of diagnosis. This hinders provision of clinical recommendations based on existing evidence. We have proposed minimum reporting requirements around acuity, contrast sensitivity, visual field method/thresholds; simulation validation to facilitate clinical utilisation.
Dementia poses a threat to public health, especially among ethnically diverse Muslim communities in the UK, with quite some peculiar nuances. Within these communities, Black Muslims in the UK face unique risks shaped by complex ethnic, religious, and socioeconomic factors. However, there is a dearth of research that specifically explores perspectives on dementia in this population. The aim of this study was to explore and understand the perspectives of Black Muslims in the UK regarding the causes and prevention of dementia using a qualitative narrative inquiry approach guided by Intersectionality Theory and the Sociocultural Health Belief Model. The study involved 15 Black Muslims (8 women, 7 men), aged between 30 and 69 years, residing across the UK, with diverse roles including actively engaged community members (n = 6), religious figures (n = 3), and caregivers (n = 2). Data were collected through semi-structured interviews conducted virtually via Microsoft Teams. Thematic analysis was performed using an iterative approach with NVivo 14 software. The analysis yielded five major themes: (1) low awareness, misconceptions and stigma surrounding dementia; (2) faith-based health beliefs as protective factors; (3) stress, loneliness, and socioeconomic pressures as risk factors; (4) religious ideals, healthy lifestyles, and everyday realities; and (5) need for culturally tailored dementia education and engagement. Participants highlighted gaps between Islamic health principles, such as the encouragement of physical activity and their everyday practices, influenced by structural barriers. Black Muslims hold nuanced beliefs about dementia, shaped by cultural, religious, and socio-environmental factors such as stigma, limited awareness and socioeconomic pressures. These dynamics influence how dementia is understood and the extent to which preventive behaviours are adopted. Promoting dementia prevention in these communities requires culturally sensitive interventions that align with religious teachings, supported by policy changes that invest in community education and embed culturally and faith-informed approaches within public health strategies.
Equitable delivery of high-quality care is challenging in mesothelioma. Previous UK audits report variable practice and outcomes. The Scottish Mesothelioma Network was launched in April 2019, funding lead clinicians and clinical nurse specialists, a weekly national multidisciplinary team meeting and service improvement driven by quality performance indicators. We report outcomes from an embedded impact assessment. A multicentre ambispective cohort study was performed, including all cases diagnosed from April 2017 to April 2022. Baseline data, treatment and survival outcomes were collected prospectively in all network cases (April 2019 to April 2022) and West of Scotland (WoS) pre-network cases (April 2017 to March 2019). Data were retrieved retrospectively for pre-network non-WoS cases via cancer networks, supplemented by Public Health Scotland registry data. Overall survival (OS) was compared between pre-network and network cohorts using restricted mean survival time (RMST). RMST differences were integrated with baseline features and treatment utilisation, including ipilimumab-nivolumab and surgery. Treatment effects were modelled by propensity score matching. 659 consecutive patients were included (pre-network n=273; network n=386). Cohort demographics were well-balanced. In the network era, data quality improved and diagnostic pathways were not delayed. Adjusted RMST was 4.13 months longer in non-epithelioid network cases (p<0.001), but did not differ in epithelioid cases. Ipilimumab-nivolumab was used more commonly in network cases (47/279 (16.8%) vs 4/154 (2.6%) performance status (PS) 0-1 pre-network), but similar RMST extension was observed in untreated patients (+4.45 months, p=0.01). RMST differences were associated with improved PS at diagnosis, but not with stage, ipilimumab-nivolumab or surgery (in 17/659 (2.6%)). Establishment of a national mesothelioma network was associated with improved OS in non-epithelioid patients. Causal inferences cannot be drawn using the methods used, but these data support wider development of specialist mesothelioma networks.
The neonatal Fc receptor (FcRn) protects IgG-based monoclonal antibodies (mAbs) from catabolism by direct binding within endosomes and facilitates their recycling to extracellular spaces. Elevated clearance of immune checkpoint inhibitors (ICIs) and other IgG-based mAbs is often observed in patients with cachexia phenotypes and is associated with worse outcomes. We sought to understand if FcRn's function is altered in cancer cachexia. Clearance of IgGs with different FcRn-binding properties were evaluated in cachectic LLC tumor-bearing (TB) and non-cachectic tumor-free mice in both wild-type and FcRn knockout backgrounds. As macrophage depletion with liposomal clodronate affects IgG pharmacokinetics only in the absence of FcRn function, we compared IgG clearance in LLC-TB and TF mice with and without macrophage ablation to assess changes in FcRn's functional status in cachectic tumor-bearing mice. We noted that the induction of IgG clearance in the presence of a cachectic tumor was dampened by the lack of FcRn engagement in whole body FcRn knockout mice. As expected, clodronate administration did not significantly affect systemic clearance of FcRn-binding IgG, though it significantly reduced clearance of FcRn-null IgG. More importantly, these effects were consistent in both TF and TB cachectic contexts. These results suggest that while FcRn accounts for a portion of the observed changes in IgG pharmacokinetics in cancer cachexia, the functional status of FcRn is not significantly different in healthy mice without tumors compared to those with LLC tumors and associated cachexia, which indicates the potential involvement of FcRn-independent mechanisms.
Trichophyton indotineae is an emerging Trichophyton species associated with extensive dermatophytosis frequently demonstrating terbinafine resistance. While early cases were reported in South Asia, T. indotineae has since spread globally, with several cases reported in the United States since 2023. To our knowledge, we describe the first cases reported in Virginia. Patients A and B each presented to the dermatology clinic with a diffuse, pruritic rash unresponsive to previous courses of topical and antifungal therapy. Both presentations raised concern for T. indotineae infection, which was confirmed with internal transcribed spacer (ITS) genome sequencing of isolates from the lesions. Both patients were initially prescribed an 8-week course of itraconazole 200 mg daily. Patient A required an additional month of treatment, but both patients had improved at follow-up. The present cases highlight several key points regarding the epidemiology, diagnosis, and management of T. indotineae infections, including continued expansion within the US, the need for ITS sequencing to distinguish T. indotineae from Trichophyton mentagrophytes and Trichophyton interdigitale, and the growing role of oral itraconazole as first-line therapy.
Pancreatic ductal adenocarcinoma (PDAC) is resistant to current immunotherapies and lacks effective anti-tumor CD8+ T cells, which is potentially due to insufficient cross-presentation by cDC1s. Here, we combine a STING agonist with anti-CTLA-4 and anti-PD-1 to achieve durable remissions and immunologic memory in multiple mouse models of poorly immunogenic PDAC. We find that tumor control does not depend on CD8+ T cells or tumor cell MHC expression but instead requires IFNγ-producing CD4+ T cells (Th1s) that are primed by dendritic cells in lymph nodes. The triple combination immunotherapy induces an accumulation of activated cDC2s carrying tumor antigen into tumor-draining lymph nodes; cDC2s are required for orthotopic tumor clearance. Intratumoral CD4+ T cells and cDC2s remain present in treatment-naive and chemotherapy-exposed human PDAC. In chemotherapy-exposed patients' blood, cDC2s outnumber cDC1s by 10-fold. Therefore, therapeutic targeting of the cDC2-CD4+ T cell-IFNγ axis could be efficacious in PDAC.
Venetoclax and azacitidine (VEN/AZA), which target BCL-2 and DNA methylation, have demonstrated substantial efficacy, particularly in older or unfit patients with acute myeloid leukemia (AML). Wilms' Tumor-1 (WT1) mRNA, measurable in peripheral blood (PB), is an established biomarker for monitoring treatment response and predicting AML prognosis. We conducted a retrospective analysis of patients with AML treated with VEN/AZA within the Okayama Hematology Study Group (OHSG). Patients who showed a marked reduction in PB WT1 mRNA levels from baseline after the first or second treatment cycle had significantly improved overall survival (OS) and progression-free survival (PFS). Moreover, achieving PB WT1 mRNA negativity-regardless of whether this occurred early or later in the therapy།was consistently associated with superior OS and PFS. These findings suggest that PB WT1 mRNA is a sensitive and reliable biomarker for predicting treatment response and long-term outcomes in patients with AML receiving VEN/AZA.
Atopic dermatitis (AD) is a chronically relapsing, complex skin disease characterized mainly by skin lesions and itch. The first-line treatment for patients with AD includes topical therapy, such as topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI). Long-term use of topical medications can be burdensome for patients, and despite these burdens, topicals remain a frequent treatment option, not only in patients with mild-to-moderate disease, but also as concomitant therapy in patients with moderate-to-severe disease. Lebrikizumab is a novel monoclonal antibody that binds with high affinity and slow off-rate to interleukin (IL)-13, thereby blocking the downstream effects of IL-13 with high potency. This review focuses on the use of topical medications in the lebrikizumab ADvocate1&2 monotherapy trials and ADjoin long-term extension study in the context of similar trials for interleukin (IL)-13/IL-4 inhibitors. In the first 16 weeks of the ADvocate1 and ADvocate2 monotherapy clinical trials, topical therapy was not permitted, and patients receiving topicals were considered nonresponders in the primary analysis. In the subsequent 36-week maintenance period, concomitant therapy was permitted at investigator discretion; however, most patients did not use TCS (TCS use: 11.9% and 9.7% for lebrikizumab treatment every 4 weeks [Q4W] and 2 weeks [Q2W], respectively). Likewise, in the ADjoin long-term extension study, concomitant therapy was permitted at investigator's discretion; however, the majority of patients did not use TCS up to 2 years of treatment (TCS use: 12.1% and 8.5% for lebrikizumab Q4W and Q2W in patients from ADvocate1&2, respectively). Treatment with lebrikizumab monotherapy improved clinical signs and symptoms of AD, and demonstrated stable long-lasting disease control with less frequent dosing (Q4W), with no or minimal use of topicals. Topical use across clinical trials for approved monotherapy biologics (dupilumab, lebrikizumab, and tralokinumab) was reported, and topical therapy was permitted in the maintenance period. For nemolizumab, there is no monotherapy data available in AD. Atopic dermatitis is a chronic skin disease that causes a range of skin manifestations, including erythematous and scaling lesions, and itch and related sleep disturbance. The main treatment options for atopic dermatitis are represented by topical treatments such as corticosteroids and calcineurin inhibitors in creams and ointment formulations. Using these topical therapies for a long time can be difficult and bothersome for patients with moderate-to-severe cases, but they are still commonly used even for severe cases. Lebrikizumab is a new type of medicine that targets a protein called interleukin-13 (IL)-13, which plays a role in atopic dermatitis. This review looks at how topical treatments were used in lebrikizumab trials. In the first 16 weeks of the ADvocate1 and ADvocate2 trials, patients were not allowed to use topical treatments, and those who did were considered nonresponders. During the next 36 weeks, patients could use topical treatments if needed, but most did not use corticosteroids. Similarly, in the ADjoin long-term study, most patients did not use corticosteroids over 2 years. Lebrikizumab treatment improved atopic dermatitis symptoms and maintained the response with little or no use of topical treatments.
T cell dysfunction is an important contributor to both multiple myeloma (MM) disease progression and failure of anti-myeloma chimeric antigen receptor (CAR) T cell and bispecific T cell engager (TCE) therapies. Overcoming T cell dysfunction is therefore key to improving MM patient outcomes. Immunomodulatory drugs (IMiDs) and cereblon E3 ligase modulatory drugs (CELMoDs) have been observed to activate T cells, and more recently reduce T cell dysfunction, however the underlying mechanisms behind this are incompletely understood. Here, using bone marrow samples from MM patients, we demonstrate a significant reduction in dysfunctional T cell populations expressing exhaustion markers such as TIGIT, upon treatment with Mezigdomide. We further demonstrate the ability of Mezigdomide to improve T cell function and cytotoxicity in primary T cell models of T cell dysfunction and bispecific TCE therapy in vitro. Using concurrent ATAC-seq, ChIP-seq, HiC and RNA-seq in primary T cells treated with Mezigdomide, we demonstrate the novel role of transcription factor Ikaros in regulating an important T cell exhaustion gene TIGIT. Finally, we demonstrate the ability of Mezigdomide to enhance survival outcomes from anti-BCMA CAR-T therapy in vivo. Overall, our data show that Mezigdomide treatment improves anti-myeloma T cell therapy efficacy and reduces T cell dysfunction by abrogating Ikaros-mediated upregulation of exhaustion genes.
The multiple swimming bells, or nectophores, of the colonial hydrozoan Nanomia septata are capable of coordinated avoidance swims in both forward and reverse directions. Individual nectophores also contribute to slower forms of swimming during foraging. Communication between a nectophore and the rest of the colony is at cone-shaped structures in the nectosome stem. The stem provides an attachment point for the nectophores and houses the simple nervous system responsible for their coordination. As revealed by immunocytochemistry, the nectosome stem has three main components: two giant axons, a distributed nerve network and a set of FMRFamide-immunoreactive nerve tracts. Whereas the nerve network is distributed throughout the stem, the nerve tracts link specific contra-lateral nectophores. Action potentials in the giant axons spread excitation rapidly along the stem, but their connection with individual nectophores is by way of the nerve network. Anatomical evidence suggests a location for the two pathways connecting the nerve network and the nectophore; one excites an epithelial impulse and leads to reverse swimming; the other provides excitation for forward swimming by feeding into a ganglion-like cluster of nerve cells. The two-way exchange of neural information between the stem and the nectophore is by way of this terminal ganglion and a single nerve leading to a nerve ring at the nectophore margin. The work presents physiological evidence for mechanisms, such as facilitation and summation, operating within a multifunctional, bidirectional nerve network, responsible for coordinating epithelial and neural signals in an early-branching nervous system containing both condensed and distributed units.
We report on the randomized portion of the phase 2, open-label CheckMate 650 trial (NCT02985957), in which docetaxel-experienced, biologically male patients with chemotherapy-refractory metastatic castration-resistant prostate cancer were randomized 2:2:1:2 to nivolumab 3 mg /kg plus ipilimumab 1 mg /kg (n = 73), nivolumab 1 mg /kg plus ipilimumab 3 mg /kg (n = 74), ipilimumab 3 mg /kg (n = 38), or cabazitaxel (n = 74). Primary endpoints were objective response rate and radiographic progression-free survival; key secondary endpoints included overall survival, prostate-specific antigen response rate, and safety. This portion of CheckMate 650 was not designed to statistically compare between cohorts. Respectively, objective response rates (95% CI) were 9.3% (2.6-22.1), 19.5% (8.8-34.9), 4.5% (0.1-22.8), and 12.2% (4.1-26.2), and median radiographic progression-free survival (95% CI) was 3.9 (2.2-7.6), 4.2 (3.3-5.6), 3.5 (2.1-5.8), and 7.9 (5.6-9.3) months. Respective incidence of grade ≥3 treatment-related adverse events was 28.8%, 30.1%, 18.4%, and 34.7%. Preliminary post hoc biomarker analyses in patients who received treatment with any immunotherapy regimen (i.e., treated with either of the nivolumab plus ipilimumab regimens or with ipilimumab alone, n = 12) identified a transcriptional signature, derived from the most highly expressed genes across cell types within select perivascular immune niches (comprising CD31+ endothelial, CD14+HLA-DR+ myeloid, and CD4+ and CD8+ T cells), which was associated with prolonged overall survival. These results provide further evidence of antitumor activity with nivolumab plus ipilimumab in select patients with metastatic castration-resistant prostate cancer and nominate a candidate prognostic biomarker that warrants confirmation in future prospective clinical trials.
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Novel treatments are needed to improve the poor prognosis of metastatic cancers. The ELEVATE Lung&UC study evaluated magrolimab plus docetaxel in patients with metastatic non-small cell lung cancer (mNSCLC), metastatic small cell lung cancer (mSCLC), and metastatic urothelial carcinoma (mUC). This phase II, open-label, multi-arm study enrolled patients who had received 1-2 (mNSCLC, mSCLC) or 2-3 prior lines of therapy (mUC) in the locally advanced/metastatic setting. A safety run-in (SRI) cohort (mNSCLC/mSCLC/mUC) followed by a phase II cohort (three groups: mNSCLC, mSCLC, mUC) were planned. Primary endpoints were incidence of treatment-emergent adverse events (TEAEs; SRI and phase II) and objective response rate (ORR; phase II). The SRI cohort (n = 9) had no dose-limiting toxicities. In phase II (mNSCLC, 29 patients; mSCLC, 42 patients; mUC, 26 patients), ORRs were 17.2% (mNSCLC), 4.8% (mSCLC), and 3.8% (mUC). Grade ≥3 magrolimab-related TEAE rates were 48.3% (mNSCLC), 47.6% (mSCLC), and 57.7% (mUC). A fatal TEAE suspected as magrolimab related (intracranial hemorrhage) occurred in one patient with mSCLC and brain metastasis (phase II). The study was closed early, which limited the interpretation of results due to short follow-up and limited endpoint maturity. Adding magrolimab to docetaxel had manageable toxicity but no meaningful improvement in efficacy. These results provide insight into the safety and efficacy of anti-CD47-containing therapies and reinforce the need for treatments that address the unmet needs of patients with previously treated metastatic solid tumors.
Relapse after chimeric antigen receptor (CAR) T-cell therapy in large B-cell lymphoma (LBCL) is associated with a dismal prognosis. Although Phase 3 trials have established CAR T-cells as standard second-line (2L) therapy, outcomes and optimal management after relapse in this setting remain unknown because no real-world data are currently available. We conducted a multicenter retrospective study using the French DESCAR-T registry, including patients with LBCL who relapsed after 2L CAR T-cell therapy with axicabtagene ciloleucel or lisocabtagene maraleucel. The objective was to describe postrelapse treatments, outcomes, and prognostic factors. Among the 893 patients treated with 2L CAR T-cells, 297 (33%) relapsed and were analyzed. Median time to relapse was 2.7 months, with 35% of these relapses occurring within 2 months. Among the 231 treated patients, bispecific antibody (BsAb)-based regimens were the most common type of salvage therapy (65%). The overall response rate after relapse was 39.1%, with a complete response rate of 27.6%. Notably, despite the use of BsAb-based therapy in 65% of patients, the median overall survival (OS2) after relapse was only 6.5 months (median progression-free survival [PFS2]: 3.4 months). Patients treated with BsAb monotherapy achieved a median OS of 7.1 months. Multivariate analysis revealed that early relapse (<6 months), an Eastern Cooperative Oncology Group (ECOG) ≥ 2, and an elevated C-reactive protein (≥30 mg/L) were independently associated with poor OS. This study represents the first real-world analysis of outcomes after relapse following 2L CAR T-cell therapy. Despite the more frequent incorporation of BsAbs into the therapeutic landscape, overall prognosis and treatment efficacy remain dismal, highlighting the urgent need for innovative therapeutic strategies and dedicated prospective trials in this emerging double-refractory population.
The aim of this review was to explore the published literature describing the presentation, characteristics, and non-pharmacological treatments of Complex Regional Pain Syndrome (CRPS) in under 18-year-olds. This scoping review was conducted in line with the Preferred Reporting Guidelines for Scoping Reviews (PRISMA-ScR). Five online databases (AMED, CINAHL + , EMBASE, EBSCO, and MEDLINE) were systematically searched with identified key terms for relevant records and screened against the eligibility criteria. Extracted data from the included studies informed a narrative synthesis. The PAGER framework was used to succinctly present gaps in the field and recommend future directions for research. Online searches yielded 140 articles. Following screening, 30 articles were included for review. Findings suggest primary symptoms included extreme pain, allodynia, and nail changes. The Budapest criteria, radiography, bone scans and laboratory examinations were commonly used diagnostic methods. Various non-pharmacological interventions were used, such as physiotherapy (home exercise), hydrotherapy, desensitisation, and cognitive behavioural therapy.  The most common symptom in children is severe pain that is disproportionate to the inciting event. Critical gaps in the evidence base such as the absence of age appropriate, validated diagnostic criteria, lack of research understanding the lived experience and impact of the condition or exploring treatment efficacy, were identified as knowledge gaps within the field. • Complex Regional Pain Syndrome is a difficult to diagnose and hard to treat pain condition. Among children, it is not well documented or understood, there are no agreed diagnostic criteria or treatment guidelines. • This scoping review summarises and presents the published research regarding presentation, diagnosis and non-pharmacological treatment of paediatric CRPS. • Issues relating to the use of treatments lacking demonstrable efficacy and the need for quick and reliable diagnoses are discussed. • Using the PAGER Framework, this review exposes critical gaps in both research (the lack of research around condition experience and treatment efficacy) and practice (the lack of validated diagnostic criteria and treatment pathways) outlining clear and urgent recommendations.
To determine whether ivermectin improves outcomes for critically and noncritically ill hospitalized patients with COVID-19. An ongoing international, multifactorial, adaptive platform, randomized, controlled trial. Hospitals in Pakistan, India, and Ireland between June 11, 2021, and September 9, 2022. Critically and noncritically ill patients. Randomized to ivermectin or no ivermectin (control). The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors. Analyses used a Bayesian cumulative logistic model. Enrollment was closed for operational futility, following external evidence suggesting no benefit with ivermectin in nonhospitalized patients with COVID-19. Among 61 critically ill patients, the median number of organ support-free days was -1, indicating death was the most common vital outcome (interquartile range [IQR], -1 to 17), for the ivermectin group and -1 (IQR, -1 to 17.25) for the control group (adjusted proportional odds ratio [OR], 0.94; 95% credible interval [CrI], 0.40-2.07) and the posterior probability of superiority to control was 44.2%. Among 89 noncritically ill patients, the median number of organ support-free days was 22 (IQR, 18.5-22) for ivermectin and 22 (IQR, 16-22) for control (adjusted proportional OR, 1.04; 95% CrI, 0.48-2.34) and the posterior probability of superiority was 53.7%. Among critically ill patients, hospital survival was 35.1% (13/37) for ivermectin and 37.5% (9/24) for control (adjusted OR, 1.00; 95% CrI, 0.39-2.32), posterior probability of superiority was 50.0%. Among noncritically ill patients, hospital survival was 84.1% (37/44) for ivermectin and 77.8% (35/45) for control (adjusted OR, 1.16; 95% CrI, 0.5-3.07), posterior probability of superiority was 63.3%. For critically and noncritically ill hospitalized patients with COVID-19, ivermectin was unlikely to improve the primary composite outcome of organ support-free days and hospital survival.