Patients with chronic lymphocytic leukemia (CLL) or monoclonal B-lymphocytosis (MBL) have impaired response to COVID-19 vaccination. A total of 258 patients (215 with CLL and 43 with MBL) had antispike antibody levels evaluable for statistical analysis. The overall seroconversion rate in patients with CLL was 94.2% (antispike antibodies ≥50 AU/mL) and 100% in patients with MBL after multiple vaccine doses. After 3 doses (post-D3) in 167 patients with CLL, 73.7% were seropositive, 17.4% had antispike antibody levels between 50 and 999 AU/mL, and 56.3% had antispike antibody levels ≥1000 AU/mL, with a median rise from 144.6 to 1800.7 AU/mL. Of patients who were seronegative post-D2, 39.7% seroconverted post-D3. For those who then remained seronegative after their previous dose, seroconversion occurred in 40.6% post-D4, 46.2% post-D5, 16.7% post-D6, and 0% after D7 or D8. After seroconversion, most had a progressive increase in antispike antibody levels. Neutralization was associated with higher antispike antibody levels, more vaccine doses, and earlier severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants; neutralizing antibody against early clade D614G was detected in 65.3%, against Delta in 52.0%, and against Omicron in 36.5%. SARS-CoV-2–specific T-cell production of interferon γ and interleukin 2 occurred in 73.9% and 60.9%, respectively, of 23 patients tested. After multiple vaccine doses, by multivariate analysis, immunoglobulin M ≥0.53 g/L, immunoglobulin subclass G3 ≥0.22 g/L and absence of current CLL therapy were independent predictors of positive serological responses. Multiple sequential COVID-19 vaccination significantly increased seroconversion and antispike antibody levels in patients with CLL or MBL.

Purpose: Women bear a disproportionate burden of persistent pain conditions when compared to men. To determine whether the hormonal environment affects the clinical experience of pain, as measured by the days per month of pelvic pain (DPelvicPM), period pain (DPeriodPM), headache (DHeadachePM) or the in vitro EC₅₀ for Interleukin-1β (IL-1β) release following TLR4 stimulation with Lipopolysaccharide from Peripheral Blood Mononuclear Cells (PBMCs). Findings were stratified according to use or non-use of the oral contraceptive pill. Patients and Methods: Fifty-six women aged 16– 35 years, with minimal or severe dysmenorrhea, and use or non-use of the OC, were enrolled. Blood was collected on two occasions in a single menstrual cycle: Days 1– 2 and Days 7– 10. Hormonal analysis for testosterone, dihydrotestosterone, dehydroepiandrosterone, Androstenedione, 3α-Androstanediol, 3β-androstanediol, estradiol, estrone, 17α-hydroxyprogesterone, progesterone, cortisol and sex-hormone binding globulin was undertaken using ultra-sensitive Liquid Chromatography Mass–Spectrometry (LC-MS). PBMCs were exposed to lipopolysaccharide (LPS) and the resulting Interleukin-1β output was determined. Results: Non-users of the OC showed a strongly inverse correlation between a reducing free androgen index (FAI) and increasing DPelvicPM (p=0.0032), DPeriodPM (p=0.013), DHeadachePM (p=0.041). Non-users of the OC showed a significant increase in DPelvicPM (p=0.049) on Days 7– 10. Modestly significant associations were found between reduced androgens and potentiated LPS-induced IL-1β (lower EC₅₀). Conclusion: This is the first study to investigate the relationship between the hormonal environment and activation of the immune system in young women with dysmenorrhoea-related pain conditions. Low androgen levels were consistently associated with increased pain. Translational implications for the findings are discussed.

To assess the safety and efficacy of an allogeneic adipose-derived mesenchymal stem cell preparation (MAG200) in the treatment of knee osteoarthritis over 12 months. A single-centre, double-blind, ascending dose, randomised controlled trial. 40 participants with moderate knee osteoarthritis were randomised to receive a single intra-articular injection of MAG200 (dose cohorts:10, 20, 50, 100 ​× ​10⁶ ​cells) or placebo. Primary objectives were safety and efficacy according to a compound responder analysis of minimal clinically important difference in pain (numerical pain rating scale [NPRS]) and function (Knee Injury and Osteoarthritis Outcome Score - Function in Daily Living subscale [KOOS_ADL]) at month 12. Secondary efficacy outcomes included changes from baseline in patient reported outcome measures and evaluation of disease-modification using quantitative MRI. Treatment was well tolerated with no treatment-related serious adverse events. MAG200 cohorts reported a greater proportion of responders than placebo and demonstrated clinical and statistically significant improvement in pain and clinically relevant improvement in all KOOS subscales. MAG200 demonstrated a reproducible treatment effect over placebo, which was clinically relevant for pain in the 10 ​× ​10⁶ dose cohort (mean difference NPRS:-2.25[95%CI:-4.47,-0.03, p ​= ​0.0468]) and for function in the 20 ​× ​10⁶ and 100 ​× ​10⁶ dose cohorts (mean difference KOOS_ADL:10.12[95%CI:-1.51,21.76, p ​= ​0.0863] and 10.81[95%CI:-1.42,23.04, p ​= ​0.0810] respectively). A trend in disease-modification was observed with improvement in total knee cartilage volume in MAG200 10, 20, and 100 ​× ​10⁶ dose cohorts, with progression of osteoarthritis in placebo, though this was not statistically significant. No clear dose response was observed. This early-phase study provides supportive safety and efficacy evidence to progress MAG200 to later-stage trial development. ACTRN12617001095358/ACTRN12621000622808.

Purpose: Dysmenorrhea is a common disorder that substantially disrupts the lives of young women. To determine whether there is evidence of activation of the innate immune system in dysmenorrhea and whether the degree of activation may be used as a biomarker for pain, we compared the responsiveness of peripheral blood mononuclear cells (PBMCs) to toll-like receptor (TLR) 2 or 4 stimulation. We also investigated whether this effect is modulated by the use of the oral contraceptive pill (OC). Patients and Methods: Fifty-six women aged 16– 35 years, with either severe or minimal dysmenorrhea, and use or non-use of the OC, were enrolled. PBMCs were collected on two occasions in a single menstrual cycle: the menstrual phase and the mid-follicular phase. PBMCs were exposed to lipopolysaccharide (LPS), a TLR4 agonist, and PAM3CSK4 (PAM), a TLR2 agonist, and the resulting interleukin-1beta (IL– 1β) output was determined. Statistical analysis compared the EC50 between groups as a measure of TLR responsiveness of PBMCs. Results: The key finding following LPS stimulation was a pain effect of dysmenorrhea (p=0.042) that was independent of use or non-use of OC, and independent of day of testing. Women with dysmenorrhea showed a large 2.15-fold (95% CI − 4.69, − 0.09) increase in IL– 1β release when compared with pain-free participants across both days. Conclusion: This is the first study to demonstrate an ex vivo immune relationship in women with dysmenorrhea-related pelvic pain. It provides evidence for the potential of immune modulation as a novel pharmacological target for future drug development in the management of dysmenorrhea.

Haploidentical hematopoietic stem cell transplant (haplo-HSCT) using posttransplant cyclophosphamide (PTCy) is appropriate for those who lack matched donors. Most studies using PTCy have been retrospective making conclusions difficult. ANZHIT-1 was a phase 2 study conducted at 6 Australian allogeneic HSCT centers. The primary end points were disease-free and overall survival at 2 years after HSCT. The reduced-intensity conditioning (RIC) included fludarabine, cyclophosphamide, and 200 cGy total body irradiation, and the myeloablative conditioning (MAC) was IV fludarabine and busulfan. PTCy, MMF and a calcineurin inhibitor (CNI) were used for graft-versus-host disease (GVHD) prophylaxis. CNIs were weaned and ceased by day +120 in eligible patients on day 60. Patients (n = 78) with hematological malignancies were included in the study, with a median follow-up of 732 days (range, 28-1728). HSCT was RIC in 46 patients and MAC in 32 patients. Disease-free survival probability at 2 years was 67.5% (95% [CI], 53.2-85.6) for MAC recipients and 68.3% (95% CI, 56.3-83.01) for RIC recipients. Transplant-related mortality (TRM) on day 100 and year 1 was 4.9% (95% CI, 1.6-15.3) and 17.9% (95% CI, 8.8-36.5), respectively, in the MAC group compared with 3.1% (95% CI, 0.8.1-12) and 11.6% (95% CI, 6-22.4), respectively, in the RIC group. The median time for elective cessation of CNI was day 142.5 days, with no excess chronic GVHD (cGVHD) or mortality. Of the evaluable patients, 71.6% discontinued immunosuppression 12 months after transplant. This prospective haplo-HSCT trial using PTCY demonstrated encouraging survival rates, indicating that early CNI withdrawal is feasible and safe.