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Allogeneic haematopoietic stem cell transplantation (alloHSCT) is safe and effective for adolescents and adults with inborn errors of immunity (IEI) with severe manifestations of their disease. The haematopoietic cell transplantation comorbidity index (HCT-CI) score predicts transplant survival in non-malignant diseases, including IEIs. We hypothesised that immune dysregulation pre-transplant may also influence transplant outcomes. We calculated the pre-transplant immune dysregulation and disease activity score (IDDA v2.1) for 82 adolescent and adult IEI patients (aged ≥ 13 years). Three-year overall survival (OS) for the whole cohort was 90% ( n  = 82) with a median follow up of 44.7 months (range 8.4 to 225.8). Events were defined as acute graft-versus-host disease (GvHD) grades II or above, chronic GvHD of any grade, graft failure, or death from any cause. Three-year event free survival (EFS) for the whole cohort was 72%. In multivariable analysis the IDDA v2.1 score pre-transplant and HCT-CI score significantly impacted OS (hazard ratio 1.08, p  = 0.028) and EFS (hazard ratio 1.04, p  = 0.0005). Importantly, 35% of this cohort had a high IDDA v2.1 score (≥ 15) and low HCT-CI score (< 3) suggesting that the risks of alloHSCT may be underestimated in a proportion of patients with IEI if the HCT-CI score is used alone. These findings support the potential for improved outcomes following successful modulation of immune dysregulation pre-transplant. The IDDA v2.1 score has utility as an objective measurement of pre-transplant immune dysregulation providing additional information regarding the risks and potential complications of alloHSCT in an individual IEI patient.

On behalf of the Board of Directors, staff, patients and children at the Child Development Centre, a warm thank-you is extended to the staff at McDonald's restaurants and to everyone who participated in \"McHappy Day\" on May 18.

My sincere thanks to the Daily News for contacting us about the hanging flower baskets that had been taken from the Child Development Centre and your subsequent articles about the theft.

Senescent tumor cells can be selectively eliminated by the BH3 mimetic, ABT‐263 (navitoclax), via senolysis. We show that ABT‐263 inhibits the interaction between anti‐apoptotic BCL‐2 family member, BCL‐XL, and pro‐apoptotic effector, BAX. This results in senescent tumor cell death in vitro and reduced tumor volume in vivo. This work highlights the utilization of senolytic agents to enhance efficacy of anticancer therapy. Tumor cells undergo senescence in response to both conventional and targeted cancer therapies. The induction of senescence in response to cancer therapy can contribute to unfavorable patient outcomes, potentially including disease relapse. This possibiliy is supported by our findings that tumor cells induced into senescence by doxorubicin or etoposide can give rise to viable tumors in vivo. We further demonstrate sensitivity of these senescent tumor cells to the senolytic ABT‐263 (navitoclax), therefore providing a “two‐hit” approach to eliminate senescent tumor cells that persist after exposure to chemotherapy or radiation. The sequential combination of therapy‐induced senescence and ABT‐263 could shift the response to therapy toward apoptosis by interfering with the interaction between BCL‐XL and BAX. The administration of ABT‐263 after either etoposide or doxorubicin also resulted in marked, prolonged tumor suppression in tumor‐bearing animals. These findings support the premise that senolytic therapy following conventional cancer therapy may improve therapeutic outcomes and delay disease recurrence.

Perfusion technologies preserve and/or improve organ viability by restoring circulation to donor organs either outside the body (machine perfusion, MP) or inside the body of the deceased donor (normothermic regional perfusion, NRP). Ethical debates surrounding perfusion raise questions about its acceptability for transplant recipients. This study explores patient perspectives on perfusion techniques and preferences regarding informed consent. Five online focus groups were conducted with 32 kidney, liver, and heart patients, both pre- and post-transplant. Sessions were analyzed using qualitative content analysis in Atlas.ti. Participants were generally accepting of MP and NRP, valuing clinical benefits. However, they were more hesitant toward NRP due to ethical concerns about post-mortem use of the donor’s body and potential emotional impacts on donor families. Drivers of acceptance were patients’ medical urgency and certainty that donor and donor family were respected. Most participants wanted to receive detailed information about perfusion techniques. While patients were broadly accepting of perfusion techniques, NRP raised more concerns than MP. To ensure ethical implementation and social acceptability as these technologies evolve, patient perspectives should be embedded into perfusion guidelines, informed consent processes, and policy development.

Rockfall modelling is an important tool for hazard analysis in steep terrain. Calibrating terrain parameters ensures that the model results more accurately represent the site-specific hazard. Parameterizing rockfall models is challenging because rockfall runout is highly sensitive to initial conditions, rock shape, size and material properties, terrain morphology, and terrain material properties. This contribution examines the mechanics of terrain impact scarring due to rockfall on the Port Hills of Christchurch, New Zealand. We use field-scale testing and laboratory direct shear testing to quantify how the changing moisture content of the loessial soils can influence its strength from soft to hard, and vice versa. We calibrate the three-dimensional rockfall model RAMMS by back-analysing several well-documented rockfall events that occurred at a site with dry loessial soil conditions. We then test the calibrated “dry” model at a site where the loessial soil conditions were assessed to be wet. The calibrated dry model over-predicts the runout distance when wet loessial soil conditions are assumed. We hypothesize that this is because both the shear strength and stiffness of wet loess are reduced relative to the dry loess, resulting in a higher damping effect on boulder dynamics. For both realistic and conservative rockfall modelling, the maximum credible hazard is usually assumed; for rockfall on loess slopes, the maximum credible hazard occurs during dry soil conditions.