Belantamab Mafodotin, Bortezomib, and Dexamethasone for Multiple Myeloma.

BACKGROUND: Belantamab mafodotin had single-agent activity in patients with relapsed or refractory multiple myeloma, a finding that supports further evaluation of the agent in combination with standard-care therapies. METHODS: In this phase 3, open-label, randomized trial, we evaluated belantamab mafodotin, bortezomib, and dexamethasone (BVd), as compared with daratumumab, bortezomib, and dexamethasone (DVd), in patients who had progression of multiple myeloma after at least one line of therapy. The primary end point was progression-free survival. Key secondary end points were overall survival, response duration, and minimal residual disease (MRD)-negative status. RESULTS: In total, 494 patients were randomly assigned to receive BVd (243 patients) or DVd (251 patients). At a median follow-up of 28.2 months (range, 0.1 to 40.0), median progression-free survival was 36.6 months (95% confidence interval [CI], 28.4 to not reached) in the BVd group and 13.4 months (95% CI, 11.1 to 17.5) in the DVd group (hazard ratio for disease progression or death, 0.41; 95% CI, 0.31 to 0.53; P<0.001). Overall survival at 18 months was 84% in the BVd group and 73% in the DVd group. An analysis of the restricted mean response duration favored BVd over DVd (P<0.001). A complete response or better plus MRD-negative status occurred in 25% of the patients in the BVd group and 10% of those in the DVd group. Grade 3 or higher adverse events occurred in 95% of the patients in the BVd group and 78% of those in the DVd group. Ocular events were more common in the BVd group than in the DVd group (79% vs. 29%); such events were managed with dose modifications, and events of worsening visual acuity mostly resolved. CONCLUSIONS: As compared with DVd therapy, BVd therapy conferred a significant benefit with respect to progression-free survival among patients who had relapsed or refractory multiple myeloma after at least one line of therapy. Most patients had grade 3 or higher adverse events. (Funded by GSK; DREAMM-7 ClinicalTrials.gov number, NCT04246047; EudraCT number, 2018-003993-29.).

Distinct Effects of Respiratory Viral Infection Models on miR-149-5p, IL-6 and p63 Expression in BEAS-2B and A549 Epithelial Cells.

Respiratory viruses cause airway inflammation, resulting in epithelial injury and repair. miRNAs, including miR-149-5p, regulate different pathological conditions. We aimed to determine how miR-149-5p functions in regulating pro-inflammatory IL-6 and p63, key regulators of airway epithelial wound repair, in response to viral proteins in bronchial (BEAS-2B) and alveolar (A549) epithelial cells. BEAS-2B or A549 cells were incubated with poly (I:C, 0.5 µg/mL) for 48 h or SARS-CoV-2 spike protein-1 or 2 subunit (S1 or S2, 1 µg/mL) for 24 h. miR-149-5p was suppressed in BEAS-2B challenged with poly (I:C), correlating with IL-6 and p63 upregulation. miR-149-5p was down-regulated in A549 stimulated with poly (I:C); IL-6 expression increased, but p63 protein levels were undetectable. miR-149-5p remained unchanged in cells exposed to S1 or S2, while S1 transfection increased IL-6 expression in BEAS-2B cells. Ectopic over-expression of miR-149-5p in BEAS-2B cells suppressed IL-6 and p63 mRNA levels and inhibited poly (I:C)-induced IL-6 and p63 mRNA expressions. miR-149-5p directly suppressed IL-6 mRNA in BEAS-2B cells. Hence, BEAS-2B cells respond differently to poly (I:C), S1 or S2 compared to A549 cells. Thus, miR-149-5p dysregulation may be involved in poly (I:C)-stimulated but not S1- or S2-stimulated increased IL-6 production and p63 expression in BEAS-2B cells.

Eating and drinking experience in patients with idiopathic pulmonary fibrosis: a qualitative study.

OBJECTIVE: To explore eating and drinking experiences of patients with idiopathic pulmonary fibrosis (IPF), the impact of any changes associated with their diagnosis and any coping mechanisms developed by patients. SETTING: Pulmonary fibrosis support groups around the UK and the regional Interstitial Lung Diseases Clinic, Newcastle upon Tyne. PARTICIPANTS: 15 patients with IPF (9 men, 6 women), median age 71 years, range (54-92) years, were interviewed. Inclusion criteria included competent adults (over the age of 18 years) with a secure diagnosis of IPF as defined by international consensus guidelines. Patients were required to have sufficient English language competence to consent and participate in an interview. Exclusion criteria were a history of other lung diseases, a history of pre-existing swallowing problem of other causes that may be associated with dysphagia and individuals with significant communication or other memory difficulties that render them unable to participate in an interview. DESIGN: A qualitative study based on semistructured interviews used purpose sampling conducted between February 2021 and November 2021. Interviews were conducted via video videoconferencing call platform or telephone call, transcribed and data coded and analysed using a reflexive thematic analysis. RESULTS: Three main themes were identified, along with several subthemes, which were: (1) Eating, as such, is no longer a pleasure. This theme mainly focused on the physical and sensory changes associated with eating and drinking and their effects and the subsequent emotional and social impact of these changes; (2) It is something that happens naturally and just try and get on with it. This theme centred on the self-determined strategies employed to manage changes to eating and drinking; and (3) What is normal. This theme focused on patients seeking information to better understand the changes in their eating and drinking and the patients' beliefs about what has changed their eating and drinking. CONCLUSIONS: To our knowledge, this is the first study to report on IPF patients' lived experience of eating and drinking changes associated with their diagnosis. Findings demonstrate that some patients have substantial struggles and challenges with eating and drinking, affecting them physically, emotionally and socially. There is a need to provide better patient information for this area and further study.

Volume loss during muscle reinnervation surgery is correlated with reduced CMAP amplitude but not reduced force output in a rat hindlimb model.

Introduction: Muscle reinnervation (MR) surgery offers rehabilitative benefits to amputees by taking severely damaged nerves and providing them with new denervated muscle targets (DMTs). However, the influence of physical changes to muscle tissue during MR surgery on long-term functional outcomes remains understudied. Methods: Our rat hindlimb model of MR surgery utilizes vascularized, directly neurotized DMTs made from the lateral gastrocnemius (LG), which we employed to assess the impact of muscle tissue size on reinnervation outcomes, specifically pairing the DMT with the transected peroneal nerve. We conducted MR surgery with both DMTs at full volume and DMTs with partial volume loss of 500 mg at the time of surgery (n = 6 per group) and measured functional outcomes after 100 days of reinnervation. Compound motor action potentials (CMAPs) and isometric tetanic force production was recorded from reinnervated DMTs and compared to contralateral naïve LG muscles as positive controls. Results: Reinnervated DMTs consistently exhibited lower mass than positive controls, while DMTs with partial volume loss showed no significant mass reduction compared to full volume DMTs (p = 0.872). CMAP amplitudes were lower on average in reinnervated DMTs, but a broad linear correlation also exists between muscle mass and maximum CMAP amplitude irrespective of surgical group (R2 = 0.495). Surprisingly, neither MR group, with or without volume loss, demonstrated decreased force compared to positive controls. The average force output of reinnervated DMTs, as a fraction of the contralateral LG's force output, approached 100% for both MR groups, a notable deviation from the 9.6% (±6.3%) force output observed in our negative control group at 7 days post-surgery. Tissue histology analysis revealed few significant differences except for a marked decrease in average muscle fiber area of reinnervated DMTs with volume loss compared to positive controls (p = 0.001). Discussion: The results from our rat model of MR suggests that tissue electrophysiology (CMAPs) and kinesiology (force production) may recover on different time scales, with volumetric muscle loss at the time of MR surgery not significantly reducing functional outcome measurements for the DMTs after 100 days of reinnervation.

Ryanodine Receptor Stabilization Therapy Suppresses Ca 2+ -Based Arrhythmias in a Novel Model of Metabolic HFpEF.

Heart Failure with preserved ejection fraction (HFpEF) is the most prevalent form of heart failure worldwide and its significant mortality is associated with a high rate of sudden cardiac death (SCD; 30% - 40%). Chronic metabolic stress is an important driver of HFpEF, and clinical data show metabolic stress as a significant risk factor for ventricular arrhythmias in HFpEF patients. The mechanisms of SCD and ventricular arrhythmia in HFpEF remain critically understudied and empirical treatment is ineffective. To address this important knowledge gap, we developed a novel preclinical model of metabolic-stress induced HFpEF using Western diet (High fructose and fat) and hypertension induced by nitric oxide synthase inhibition (with L-NAME) in wildtype C57BL6/J mice. After 5 months, mice display all clinical characteristics of HFpEF and present with stress-induced sustained ventricular tachycardia (VT). Mechanistically, we found a novel pattern of arrhythmogenic intracellular Ca 2+ handling that is distinct from the well-characterized changes pathognomonic for heart failure with reduced ejection fraction. In addition, we show that the transverse tubular system remains intact in HFpEF and that arrhythmogenic, intracellular Ca 2+ mobilization becomes hyper-sensitive to ß- adrenergic activation. Finally, in proof-of-concept experiments we show in vivo that the clinically used intracellular calcium stabilizer dantrolene, which acts on the Ca 2+ release channels of the sarcoplasmic reticulum (SR), the ryanodine receptors, acutely prevents stress-induced VT in HFpEF mice. Therapeutic control of SR Ca 2+ leak may present a novel mechanistic treatment approach in metabolic HFpEF.

Personalized medicine in a community health system: the NorthShore experience.

Genomic and personalized medicine implementation efforts have largely centered on specialty care in tertiary health systems. There are few examples of fully integrated care systems that span the healthcare continuum. In 2014, NorthShore University HealthSystem launched the Center for Personalized Medicine to catalyze the delivery of personalized medicine. Successful implementation required the development of a scalable family history collection tool, the Genetic and Wellness Assessment (GWA) and Breast Health Assessment (BHA) tools; integrated pharmacogenomics programming; educational programming; electronic medical record integration; and robust clinical decision support tools. To date, more than 225,000 patients have been screened for increased hereditary conditions, such as cancer risk, through these tools in primary care. More than 35,000 patients completed clinical genetic testing following GWA or BHA completion. An innovative program trained more than 100 primary care providers in genomic medicine, activated with clinical decision support and access to patient genetic counseling services and digital healthcare tools. The development of a novel bioinformatics platform (FLYPE) enabled the incorporation of genomics data into electronic medical records. To date, over 4,000 patients have been identified to have a pathogenic or likely pathogenic variant in a gene with medical management implications. Over 33,000 patients have clinical pharmacogenomics data incorporated into the electronic health record supported by clinical decision support tools. This manuscript describes the evolution, strategy, and successful multispecialty partnerships aligned with health system leadership that enabled the implementation of a comprehensive personalized medicine program with measurable patient outcomes through a genomics-enabled learning health system model that utilizes implementation science frameworks.

Tissue-resident B cells orchestrate macrophage polarisation and function.

B cells play a central role in humoral immunity but also have antibody-independent functions. Studies to date have focused on B cells in blood and secondary lymphoid organs but whether B cells reside in non-lymphoid organs (NLO) in homeostasis is unknown. Here we identify, using intravenous labeling and parabiosis, a bona-fide tissue-resident B cell population in lung, liver, kidney and urinary bladder, a substantial proportion of which are B-1a cells. Tissue-resident B cells are present in neonatal tissues and also in germ-free mice NLOs, albeit in lower numbers than in specific pathogen-free mice and following co-housing with 'pet-store' mice. They spatially co-localise with macrophages and regulate their polarization and function, promoting an anti-inflammatory phenotype, in-part via interleukin-10 production, with effects on bacterial clearance during urinary tract infection. Thus, our data reveal a critical role for tissue-resident B cells in determining the homeostatic 'inflammatory set-point' of myeloid cells, with important consequences for tissue immunity.

Diagnosis and management of endothelial disorders following haematopoietic stem cell transplantation.

Haematopoietic stem cell transplantation is a mainstay of therapy for numerous malignant and nonmalignant diseases. Endothelial activation and dysfunction occur after stem cell transplantation, driven by various patient- and transplant-specific factors. This can manifest as one of the relatively uncommon endothelial injury syndromes, such as sinusoidal obstruction syndrome, transplant-associated thrombotic microangiopathy, idiopathic pneumonia syndrome, capillary leak syndrome, engraftment syndrome or posterior reversible encephalopathy syndrome. This review focuses on the pathogenesis, classification and diagnosis of these disorders, as well as provides guidance on risk mitigation and treatment.

Predictors of post traumatic growth in allogeneic hematopoietic stem cell transplantation survivors: a cross-sectional survey.

AIMS: Given the increasing number of Hematopoietic Stem Cell Transplantations (HSCT) performed world-wide, the increasing likelihood of survival following HSCT, and the profound physical, psychosocial, and emotional impact of HSCT on survivors, their carers and families, it is important to identify factors that may contribute to or support post-traumatic growth (PTG) after transplant. In this study, we aimed to investigate the prevalence of PTG in an Australian cohort of long-term allogeneic HSCT survivors and describe associations between PTG and relevant clinical, sociodemographic and psychological variables. METHODS: This was a large, multi-centre, cross sectional survey of Australian HSCT-survivors inviting all those transplanted in New South Wales between 2000 and 2012. Respondents completed the PTG Inventory (PTGI), the Sydney Post-BMT Survey, FACT-BMT, DASS 21, The Chronic Graft versus Host Disease (GVHD) Activity Assessment-Patient Self-Report (Form B), the Lee Chronic GVHD Symptom Scale, and the Fear of Cancer Recurrence Scale. Data was analysed using independent t-tests, one-way analysis of variance, and pearson's correlations, and hierarchical multiple regression adjusted for potential confounders and to ascertain independent associations of explanatory variables with PTG. RESULTS: Of 441 respondents, 99% reported some level of PTG with 67% reporting moderate to high levels of PTG. Female gender, younger age, complementary therapy use, anxiety, psychological distress and psychosocial care, and higher quality of life were associated with higher levels of PTG. Importantly, we also found that PTG was not associated with either chronic GVHD or post-HSCT morbidity. CONCLUSIONS: In this study - the largest study of PTG in long-term allogeneic HSCT survivors - we found that growth appears ubiquitous, with 99% of survivors reporting some degree of PTG and 67% reporting moderate-high levels of PTG. Importantly, we found no association with GVHD or chronic physical post-HSCT morbidity, or adverse financial, occupational or sexual impacts. This suggests that it is the necessity for and experience of, HSCT itself that foments personal growth. Accordingly, healthcare professionals should be alert to the profound and wide-ranging impact of HSCT - and the degree to which survivor's may experience PTG. Identifying interventions that may assist HSCT survivors cope and building their resilience is of utmost importance.

Decisional Regret in Long-Term Australian Allogeneic Hematopoietic Stem Cell Transplantation Survivors: A Cross-Sectional Survey.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an intensive but effective treatment for malignant and non-malignant diseases. However, long-term survival often comes at a cost, with survivors experiencing chronic morbidity and are at risk of relapse and secondary malignancy. This study aimed to describe decisional regret in a large cohort of Australian long-term allo-HSCT survivors. A cross-sectional survey was conducted with 441 adults in New South Wales, assessing quality of life (QoL), psychological, social, demographic, and clinical variables. Less than 10% of survivors expressed regret, with chronic graft-versus-host disease being the most important clinical factor. Psycho-socioeconomic factors such as depression, lower QoL scores, lower household income, higher treatment burden, and not resuming sex post-HSCT were also associated with regret. Findings highlight the need for valid informed consent and ongoing follow-up and support for allo-HSCT survivors dealing with life post-transplant. Nurses and healthcare professionals play a critical role in addressing decisional regret in these patients.

The efficacy of biosynthesized silver nanoparticles against Pseudomonas aeruginosa isolates from cystic fibrosis patients.

The high antibiotic resistance of Pseudomonas aeruginosa (PA) makes it critical to develop alternative antimicrobial agents that are effective and affordable. One of the many applications of silver nanoparticles (Ag NPs) is their use as an antimicrobial agent against bacteria resistant to common antibiotics. The key purpose of this research was to assess the antibacterial and antibiofilm effectiveness of biosynthesized Ag NPs against six biofilm-forming clinically isolated strains of PA and one reference strain (ATCC 27853). Ag NPs were biosynthesized using a seed extract of Peganum harmala as a reducing agent. Ag NPs were characterized by Ultraviolet-visible (UV-Vis) spectroscopy and scanning transmission electron microscopy (STEM). The effect of Ag NPs on biofilm formation and eradication was examined through micro-titer plate assays, and the minimal inhibitory (MIC) and minimum bactericidal (MBC) concentrations determined. In addition, real-time polymerase chain reactions (RT-PCR) were performed to examine the effects of Ag NPs on the expression of seven PA biofilm-encoding genes (LasR, LasI, LssB, rhIR, rhII, pqsA and pqsR). The biosynthesized Ag NPs were spherically-shaped with a mean diameter of 11 nm. The MIC for each PA strain was 15.6 µg/ml, while the MBC was 31.25 µg/ml. All PA strains exposed to Ag NPs at sub-inhibitory concentrations (0.22-7.5 µg/ml) showed significant inhibitory effects on growth and biofilm formation. Biomass and biofilm metabolism were reduced dependent on Ag NP concentration. The expression of the quorum-sensing genes of all strains were significantly reduced at an Ag NP concentration of 7.5 µg/ml. The results demonstrate the extensive in-vitro antibacterial and antibiofilm performance of Ag NPs and their potential in the treatment of PA infection. It is recommended that future studies examine the possible synergy between Ag NPs and antibiotics.

Not Your Everyday Duodenal Ulcer: Massive Gastrointestinal Bleed Secondary to Extramedullary Plasma Cell Myeloma.

The differential for gastrointestinal (GI) bleeding is broad, ranging from peptic ulcers and Helicobacter pylori infection to variceal hemorrhage and neoplasms. The rarer causes of GI bleeds are frequently overlooked and as such can ultimately be more dangerous. Extramedullary multiple myeloma, an atypical plasma cell dyscrasia arising outside of the bone marrow, involves the GI tract in <5% of cases and often presents with nonspecific symptoms. We describe a rare case of such GI involvement of a plasma cell tumor, with subsequent transmural duodenal ulceration involving the gastroduodenal artery, ultimately resulting in a fatal GI bleed.

Enveloped viruses pseudotyped with mammalian myogenic cell fusogens target skeletal muscle for gene delivery.

Entry of enveloped viruses into cells is mediated by viral fusogenic proteins that drive membrane rearrangements needed for fusion between viral and target membranes. Skeletal muscle development also requires membrane fusion events between progenitor cells to form multinucleated myofibers. Myomaker and Myomerger are muscle-specific cell fusogens but do not structurally or functionally resemble classical viral fusogens. We asked whether the muscle fusogens could functionally substitute for viral fusogens, despite their structural distinctiveness, and fuse viruses to cells. We report that engineering of Myomaker and Myomerger on the membrane of enveloped viruses leads to specific transduction of skeletal muscle. We also demonstrate that locally and systemically injected virions pseudotyped with the muscle fusogens can deliver µDystrophin to skeletal muscle of a mouse model of Duchenne muscular dystrophy and alleviate pathology. Through harnessing the intrinsic properties of myogenic membranes, we establish a platform for delivery of therapeutic material to skeletal muscle.

Impact of Airway Virus in Severe Asthmatic Patients: A Pilot Study.

The lungs have their own microbiota which seems to be altered in disease processes such as asthma. Viral infection accounts for many asthma exacerbations. Little is known about the lung virome, and the role that viruses play in non-exacerbating asthmatics. We aimed to assess if detection of virus in bronchoscopy samples of asthmatic patients in a non-exacerbating state influences their asthma control and modulates airway cytokine composition. Patients were recruited from a specialist asthma clinic and underwent bronchoscopy with standardised bronchoalveolar lavage (BAL). Viral analysis was performed; cell differential and cytokine levels were measured. Forty-six samples were obtained of which 10.8% demonstrated evidence of airway virus, and 91.3% of patients in the cohort were classed as severe asthmatics. Oral steroid use was significantly higher in severe asthmatic patients with virus detected, and the forced expiratory volume in one second tended to be lower in the virus-detected group. It was also found that BAL interleukin-13 and tumor necrosis factor-α levels were significantly higher in severe asthmatic patients with virus detected. Our results suggest that in severe asthmatics in a non-exacerbating state, the presence of virus resulted in overall poorer asthma control. The pattern of cytokine elevation seen in asthmatic patients with virus detected may provide insight to the pathophysiology involved.

The importance of frailty assessment in multiple myeloma: a position statement from the Myeloma Scientific Advisory Group to Myeloma Australia.

Multiple myeloma (MM) is a disease of older people, yet factors relating to comorbidity and frailty may threaten treatment tolerability for many of this heterogenous group. There has been increasing interest in defining specific and clinically relevant frailty assessment tools within the MM population, with the goal of using these frailty scores, not just as a prognostic instrument, but also as a predictive tool to allow for a frailty-adapted treatment approach. This paper reviews the various frailty assessment frameworks used in the evaluation of patients with MM, including the International Myeloma Working Group Frailty Index (IMWG-FI), the Mayo Frailty Index and the simplified frailty scale. While the IMWG-FI remains the most widely accepted tool, the simplified frailty scale is the most user-friendly in busy day-to-day clinics based on its ease of use. This paper summarises the recommendations from the Myeloma Scientific Advisory Group (MSAG) of Myeloma Australia, on the use of frailty assessment tools in clinical practice and proposes a frailty-stratified treatment algorithm to aid clinicians in tailoring therapy for this highly heterogeneous patient population.

Skeletal Muscle Measurements in Pediatric Hematology and Oncology: Essential Components to a Comprehensive Assessment.

Children with hematologic and oncologic health conditions are at risk of impaired skeletal muscle strength, size, and neuromuscular activation that may limit gross motor performance. A comprehensive assessment of neuromuscular function of these children is essential to identify the trajectory of changes in skeletal muscle and to prescribe therapeutic exercise and monitor its impact. Therefore, this review aims to (a) define fundamental properties of skeletal muscle; (b) highlight methods to quantify muscle strength, size, and neuromuscular activation; (c) describe mechanisms that contribute to muscle strength and gross motor performance in children; (d) recommend clinical assessment measures; and (e) illustrate comprehensive muscle assessment in children using examples of sickle cell disease and musculoskeletal sarcoma.

Treatment of patients with Waldenström macroglobulinaemia: clinical practice update from the Myeloma Foundation of Australia Medical and Scientific Advisory Group.

Waldenström macroglobulinaemia (WM) is an indolent B-cell malignancy characterised by the presence of IgM paraprotein, bone marrow infiltration by clonal small B lymphocytes with plasmacytic differentiation and the MYD88 L265P mutation in >90% of cases. Traditionally, WM has been treated with chemoimmunotherapy. Recent trials have demonstrated the efficacy and safety of Bruton tyrosine kinase inhibitors in WM, both as monotherapy and in combination with other drugs. There is emerging evidence on the use of other agents including B-cell lymphoma 2 inhibitors and on the treatment of rare presentations of WM. In this update, the Medical and Scientific Advisory Group of Myeloma Australia reviews the available evidence on the treatment of WM since the last publication in 2017 and provides specific recommendations to assist Australian clinicians in the management of this disease.

Influence of fecal microbial transplant (FMT) between male and female rats on methamphetamine-induced hyperthermia.

OBJECTIVE: To investigate the effect of bidirectional fecal microbial transplant (FMT) between male and female rats on methamphetamine (MA)-induced hyperthermia. METHODS: FMT was performed between male and female rats prior to MA (10 mg/kg, sc) treatment. Core body temperature, plasma drug and norepinephrine (NE) levels were measured and compared between treatment groups. 16S rRNA gene sequencing of bacterial communities between male and female rats was performed. RESULTS: MA treatment resulted in significantly higher core body temperatures in male groups (control and FMT-treated) compared to MA-treated female groups (control and FMT-treated). Plasma concentrations of MA and amphetamine were higher in females than males. Whereas, plasma norepinephrine (NE) levels were not different between male and female rats 90 minutes after MA treatment. At the phyla level, the microbiome of male and female control rats were dominated by Firmicutes and Bacteroidetes. Males had a higher relative abundance of Firmicutes and lower relative abundances of Bacteroidetes than females. The FMT procedure changed the recipient group towards their donor with males getting closer to their donors than females. In the control groups following MA treatment, Firmicutes increased and Bacteroides decreased in females and males. Conversely, in the FMT treatment groups following MA treatment, Firmicutes decreased while Bacteroidetes increased in females and males. CONCLUSIONS: Although definite differences in the structure and diversity of the gut microbiome were observed using 16S rRNA gene sequencing of bacterial communities between male and female rats, these differences do not seem to contribute to the sex-based differences in MA-induced hyperthermia.

Caspase-1 and the inflammasome promote polycystic kidney disease progression.

We and others have previously shown that the presence of renal innate immune cells can promote polycystic kidney disease (PKD) progression. In this study, we examined the influence of the inflammasome, a key part of the innate immune system, on PKD. The inflammasome is a system of molecular sensors, receptors, and scaffolds that responds to stimuli like cellular damage or microbes by activating Caspase-1, and generating critical mediators of the inflammatory milieu, including IL-1ß and IL-18. We provide evidence that the inflammasome is primed in PKD, as multiple inflammasome sensors were upregulated in cystic kidneys from human ADPKD patients, as well as in kidneys from both orthologous (PKD1 RC/RC or RC/RC) and non-orthologous (jck) mouse models of PKD. Further, we demonstrate that the inflammasome is activated in female RC/RC mice kidneys, and this activation occurs in renal leukocytes, primarily in CD11c+ cells. Knock-out of Casp1, the gene encoding Caspase-1, in the RC/RC mice significantly restrained cystic disease progression in female mice, implying sex-specific differences in the renal immune environment. RNAseq analysis implicated the promotion of MYC/YAP pathways as a mechanism underlying the pro-cystic effects of the Caspase-1/inflammasome in females. Finally, treatment of RC/RC mice with hydroxychloroquine, a widely used immunomodulatory drug that has been shown to inhibit the inflammasome, protected renal function specifically in females and restrained cyst enlargement in both male and female RC/RC mice. Collectively, these results provide evidence for the first time that the activated Caspase-1/inflammasome promotes cyst expansion and disease progression in PKD, particularly in females. Moreover, the data suggest that this innate immune pathway may be a relevant target for therapy in PKD.

Exploring the impact of elexacaftor-tezacaftor-ivacaftor treatment on opinions regarding airway clearance techniques and nebulisers: TEMPO a qualitative study in children with cystic fibrosis, their families and healthcare professionals.

BACKGROUND: Cystic fibrosis (CF) is a genetic condition caused by variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that primarily impacts the lungs. Treatments historically have been symptomatic to improve airway clearance and treat infection. However, CFTR modulator drugs have recently been developed that target the underlying defect. The triple combination of elexacaftor-tezacaftor-ivacaftor (ETI) was approved in 2020 in England for over 80% of people with CF aged over 12 years and in 2022 extended to those over 6 years. ETI treatment is associated with substantial improvements in lung function. The experience of children with CF starting on ETI or their views regarding future treatments have not been well studied. This study aimed to explore the opinions of children with CF, their parents/carers and healthcare professionals (HCPs) on the impact of ETI, airway clearance techniques (ACTs) and nebulised treatments. METHODS: Semistructured qualitative interviews were performed with 10 children with CF, 7 parents/carers and 10 HCPs. Audio recordings were transcribed and analysed using reflexive thematic analysis. RESULTS: Four main themes were identified: 'Kaftrio changed my life', 'Your entire life is dictated by the CF timetable', 'Simplifying treatment-hopes and fears' and 'Kaftrio is a game-changer' along with several subthemes and an overarching theme of 'I still can't get my head around how three tablets can do what Kaftrio done'. CONCLUSIONS: Despite the highly positive impact of ETI on the health of children with CF some concerns remain about the longer-term outcomes of reducing ACTs or nebulised treatments. ETI has prompted a shift in treatment for many and offers an opportunity to personalise approaches.