Improving semi-arid agroecosystem services with cover crop mixes.

Winter wheat (Triticum aestivum, L.) production in the semi-arid US Northern High Plains (NHP) is challenged by frequent droughts and water-limited, low fertility soils. Composted cattle manure (compost) and cover crops (CC) are known to provide agroecosystem services such as improved soil health, and in the CC case, increased plant diversity, and competition with weedy species. The main concern of planting CC in winter wheat fallow rotation in regions that are more productive than the NHP, however, is the soil moisture depletion. It is unknown however, whether addition of CC to compost-amended soils in the NHP will improve soil properties and agroecosystem health without compromising already low soil water content. The main objective of this study was to assess the effects of four CC treatments amended with compost (45 Mg ha-1) or inorganic fertilizer (IF) (.09 Mg ha-1 mono-ammonium phosphate, 11-52-0 and 1.2 Mg ha-1ammonium sulfate, 21-0-0) on the presence of weeds, soil and plant total carbon (C), nitrogen (N), and biological dinitrogen (N2) fixation (BNF). Mycorrhizal Mix (MM), Nitrogen Fixer Mix (NF), Soil Building Mix (SB), a monoculture of phacelia (Phacelia tanacetifolia Benth L.) (PH), and a no CC control (no CC) were grown in native soil kept at 7% soil moisture in a greenhouse for a period of nine weeks. When amended with compost, MM was the most beneficial (48 g m-2 BNF and 1.7% soil C increase). SB had the highest germination, aboveground biomass, and decreased weed biomass by 60%. It also demonstrated the second highest amount of BNF (40 g m-2) and soil C increase by 1.5%. On contrary, IF hindered BNF by almost 70% in all legume-containing CC treatments and reduced soil C by 15%.

The Effect of Botulinum Neurotoxin-A (BoNT-A) on Muscle Strength in Adult-Onset Neurological Conditions with Focal Muscle Spasticity: A Systematic Review.

Botulinum neurotoxin-A (BoNT-A) injections are effective for focal spasticity. However, the impact on muscle strength is not established. This study aimed to investigate the effect of BoNT-A injections on muscle strength in adult neurological conditions. Studies were included if they were Randomised Controlled Trials (RCTs), non-RCTs, or cohort studies (n ≥ 10) involving participants ≥18 years old receiving BoNT-A injection for spasticity in their upper and/or lower limbs. Eight databases (CINAHL, Cochrane, EMBASE, Google Scholar, Medline, PEDro, Pubmed, Web of Science) were searched in March 2024. The methodology followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered in the Prospective Register of Systematic Reviews (PROSPERO: CRD42022315241). Quality was assessed using the modified Downs and Black checklist and the PEDro scale. Pre-/post-injection agonist, antagonist, and global strength outcomes at short-, medium-, and long-term time points were extracted for analysis. Following duplicate removal, 8536 studies were identified; 54 met the inclusion criteria (3176 participants) and were rated as fair-quality. Twenty studies were analysed as they reported muscle strength specific to the muscle injected. No change in agonist strength after BoNT-A injection was reported in 74% of the results. Most studies' outcomes were within six weeks post-injection, with few long-term results (i.e., >three months). Overall, the impact of BoNT-A on muscle strength remains inconclusive.

Developing and validating a discrete-event simulation model of multiple myeloma disease outcomes and treatment pathways using a national clinical registry.

Multiple myeloma is a haematological malignancy typically characterised by neoplastic plasma cell infiltration of the bone marrow. Treatment for multiple myeloma consists of multi-line chemotherapy with or without autologous stem cell transplantation and has been rapidly evolving in recent years. However, clinical trials are unable to provide patients and clinicians with long-term prognostic information nor policymakers with the full body of evidence needed to perform economic evaluation of new therapies or make reimbursement decisions. To address these limitations of the available evidence, this study aimed to develop and validate the EpiMAP Myeloma model, a discrete-event simulation model of multiple myeloma disease outcomes and treatment pathways. Risk equations were estimated using the Australian and New Zealand Myeloma & Related Diseases Registry after multiple imputation of missing data. Risk equation coefficients were combined with multiple myeloma patients at diagnosis from the Registry to perform the simulation. The model was validated with 100 bootstraps of an out-of-sample prediction analysis using a 70/30 split of the 4,121 registry patients diagnosed between 2009 and 2023, resulting in 2,884 and 1,237 patients in the training and validation cohorts, respectively. For 90% of the 120 months in the 10-year post-diagnosis period, there was no significant difference in overall survival between the validation and simulated cohorts. These results highlight that the EpiMAP Myeloma model is robust at predicting multiple myeloma disease outcomes and treatment pathways in Australia & New Zealand. In the future, clinicians will be able to use the EpiMAP Myeloma model to provide personalised estimates of life expectancy to patients based on their specific characteristics, disease stage, and response to treatment. Policymakers will also be able to use the model to perform economic evaluation, to forecast the number of patients receiving treatment at different stages, and to determine the downstream impact of listing new, effective therapies.

Variation in immunoglobulin use and impact on survival in myeloma.

Serious infection is common in patients with multiple myeloma due to immune deficiency from the underlying disease and/or its treatment. Immunoglobulin replacement is one approach to reduce infection risk in these patients. However, few real-world data exist on its use in patients with myeloma. We investigated immunoglobulin use in Australia, New Zealand and Asia-Pacific using registry data and explored its association with survival outcomes. A total of 2374 patients with a median follow-up time of 29.5 months (interquartile range 13.3-54.3 months) were included in the analysis - 1673 from Australia, 313 Korea, 281 New Zealand and 107 Singapore. Overall, 7.1% of participants received immunoglobulin replacement within 24 months of diagnosis. Patients who received immunoglobulin replacement were likely to be younger, had lower baseline IgG levels (excluding paraprotein), were more likely to have baseline hypogammaglobulinaemia, baseline severe hypogammaglobulinaemia and abnormal baseline fluorescent in-situ hybridisation status, receive first-line myeloma treatment with immunomodulatory drugs or anti-CD38 therapy and undergo upfront autologous stem cell transplant. In our patient cohort, the use of immunoglobulin was not associated with overall survival benefit at the time of last follow-up (adjusted hazard ratio 0.72, 95% CI 0.46-1.14, p = 0.16). Understanding treatment approaches in clinical practice can help support future planning and provision of immunoglobulin resources.

Cancer Nurses' Voices and Recommendations to Address Workforce Challenges: A Qualitative Analysis.

OBJECTIVES: Amidst the fulfilment of making a positive impact on patients' lives, cancer nurses also contend with high workloads, limited resources, and barriers to career advancement. Understanding the perceptions of cancer nurses is essential in addressing these challenges and fostering an environment that promotes both professional satisfaction and optimal patient care. Our aim was to explore Australian cancer nurses' experiences and perspectives of workforce challenges and their proposed solutions to address them. METHODS: The Cancer Nurses Society Australia workforce cross-sectional survey was distributed online in 2022 through professional networks and social media. Free text responses to open-ended questions were analyzed using qualitative content analysis and inductive processes. RESULTS: Responses from 601 cancer nurses highlight the intricate interplay between rewards and obstacles experienced by the profession and identify key areas for improvement. Positive and negative quotes highlight the passion of cancer nurses which were summarized into themes and subthemes: 1) Finding fulfilment while struggling against the tide. While feeling undervalued and facing workload pressures, burnout and limited opportunities for career progression, nurses express love for their jobs, finding it rewarding yet emotionally challenging. 2) Grassroots solutions versus organizational inertia. Proposed solutions included addressing nurse-to-patient ratios, proactive succession planning, more specific education, dedicated time for learning, and mentorship and career development programs. Perceived barriers to initiatives included lethargic management and resistance to change. Networking opportunities, appropriate remuneration, and interdisciplinary teamwork with an appreciation of individual expertise are desired. CONCLUSIONS: Our findings give a voice to the cancer nurses of Australia. Nurses identified a range of solutions to address workforce challenges. IMPLICATIONS FOR NURSING PRACTICE: Addressing the systemic issues that contribute to high workload and impede nurses' well-being and their recognition, and promoting policies to support professional growth will increase satisfaction, enhance patient care outcomes, and contribute to a sustainable workforce.

The impact of biomarkers of malignancy (IMWG SLiM criteria) in myeloma in a real-world population: Clinical characteristics, therapy and outcomes from the Australian and New Zealand Myeloma and Related Diseases Registry (ANZ MRDR).

A decade after International Myeloma Working Group (IMWG) biomarkers (SLiM criteria) were introduced, this real-world study examined their impact on diagnosis, therapy and outcomes in myeloma. Using the ANZ MRDR, 3489 newly diagnosed patients from 2013 to 2023, comprising 3232 diagnosed by CRAB ('CRAB patients', including 1758 who also satisfied ≥1 SLiM criteria) and 257 by SLiM ('SLiM patients') criteria were analysed. CRAB patients had higher R-ISS and lower performance status, with no difference in cytogenetic risk. SLiM patients had improved progression-free survival (PFS, 37.5 vs. 32.2 months, hazard ratio [HR] 1.31 [1.08-1.59], p = 0.003), overall survival (80.9 vs. 73.2 months, HR 1.64 [1.26-2.13], p < 0.001) and PFS2 (54.6 vs. 40.3 months, HR 1.51 [1.22-1.86], p < 0.001) compared with CRAB patients, partially explained by earlier diagnosis, with no differential impact between the plasma cell and light-chain criteria on PFS. However, 34% of CRAB patients did not manifest SLiM characteristics, raising the possibility that SLiM features are associated with different biological behaviours contributing to a better prognosis, for example, improved PFS2 in SLiM patients suggested less disease resistance at first relapse. These data support earlier initiation of therapy by SLiM. The superior survival outcomes of SLiM versus CRAB patients highlight the importance of defining these subgroups when interpreting therapeutic outcomes at induction and first relapse.

Clinical effectiveness and analytical quality of a national point-of-care testing network for sexually transmitted infections integrated into rural and remote primary care clinics in Australia, 2016-2022: an observational program evaluation.

Background: To address inequitable diagnostic access and improve time-to-treatment for First Nations peoples, molecular point-of-care (POC) testing for chlamydia, gonorrhoea and trichomonas was integrated into 49 primary care clinics across Australia. We conducted an observational evaluation to determine clinical effectiveness and analytical quality of POC testing delivered through this national program. Methods: We evaluated (i) implementation by measuring trends in mean monthly POC testing; ii) clinical effectiveness by comparing proportions of positive patients treated by historical control/intervention period and by test type, and calculated infectious days averted; (iii) analytical quality by calculating result concordance by test type, and proportion of unsuccessful POC tests. Findings: Between 2016 and 2022, 46,153 POC tests were performed; an increasing mean monthly testing trend was observed in the first four years (p < 0.0001). A greater proportion of chlamydia/gonorrhoea positives were treated in intervention compared with historical control periods (≤2 days: 37% vs 22% [RR 1.68; 95% CI 1.12, 2.53]; ≤7 days: 48% vs 30% [RR 1.6; 95% CI 1.10, 2.33]; ≤120 days: 79% vs 54% [RR 1.46; 95% CI 1.10, 1.95]); similarly for trichomonas positives and by test type. POC testing for chlamydia, gonorrhoea and trichomonas averted 4930, 5620 and 7075 infectious days, respectively. Results concordance was high [99.0% (chlamydia), 99.3% (gonorrhoea) and 98.9% (trichomonas)]; unsuccessful POC test proportion was 1.8% for chlamydia/gonorrhoea and 2.1% for trichomonas. Interpretation: Molecular POC testing was successfully integrated into primary care settings as part of a routinely implemented program achieving significant clinical benefits with high analytical quality. In addition to the individual health benefits of earlier treatment, fewer infective days could contribute to reduced transmissions in First Nations communities. Funding: This work was supported by an Australian National Health and Medical Research Council Partnership Grant (APP1092503), the Australian Government Department of Health, Western Australia and Queensland Departments of Health.

A backward cycling programme for people with Parkinson's disease: a feasibility and preliminary results study.

OBJECTIVE: To assess the feasibility of backward cycling for people with Parkinson's disease. Secondary objectives were to assess changes in gait and balance following a 6-week program. DESIGN: A single-group prospective pre-test, post-test study with 1-month follow-up. SUBJECTS/PATIENTS: Twenty-six people with Parkinson's disease (mean age: 69 (7.74) years, gender: 83% males, time since diagnosis: 6 (4.44) years). METHODS: Participants pedaled backward on a stationary bicycle for 30 minutes at moderate intensity twice a week for 6 weeks. Feasibility was assessed by acceptability, suitability, and burden. Data collected at pre- and post-intervention with 1-month follow-up included backward stepping response variables, forward/backward gait variables, Mini-Balance Evaluation Systems Test (MBT), and 6 Minute Walk Test. RESULTS: There was a high retention rate (95.8%) and adherence rate (100%) with one adverse event and minimal burden. Significant improvements were seen in step count and excursion distance during backward stepping responses, forward and backward gait velocity, forward step length, and the Mini-BESTest. CONCLUSION: Backward cycling was a feasible intervention for people with Parkinson's disease, demonstrating low burden with high retention and adherence rates, and it is a safe exercise with the potential for benefits in gait and balance variables.

The establishment of a multiple myeloma clinical registry in the Asia-Pacific region: The Asia-Pacific Myeloma and Related Diseases Registry (APAC MRDR).

BACKGROUND: Multiple myeloma (MM) is the second most common haematological cancer worldwide. Along with related diseases including monoclonal gammopathy of undetermined significance (MGUS), plasma cell leukaemia (PCL) and plasmacytoma, MM incidence is rising, yet it remains incurable and represents a significant disease burden. Clinical registries can provide important information on management and outcomes, and are vital platforms for clinical trials and other research. The Asia-Pacific Myeloma and Related Diseases Registry (APAC MRDR) was developed to monitor and explore variation in epidemiology, treatment regimens and their impact on clinical outcomes across this region. Here we describe the registry's design and development, initial data, progress and future plans. METHODS: The APAC MRDR was established in 2018 as a multicentre collaboration across the Asia-Pacific, collecting prospective data on patients newly diagnosed with MM, MGUS, PCL and plasmacytoma in Korea, Singapore, Malaysia and Taiwan, with China recently joining. Development of the registry required a multidisciplinary team of clinicians, researchers, legal and information technology support, and financial resources, as well as local clinical context from key opinion leaders in the APAC region. Written informed consent is obtained and data are routinely collected throughout treatment by hospital staff. Data are stored securely, meeting all local privacy and ethics requirements. Data were collected from October 2018 to March 2024. RESULTS: Over 1700 patients from 24 hospitals have been enrolled onto the APAC MRDR to date, with the majority (86%) being newly diagnosed with MM. Bortezomib with an immunomodulatory drug was most frequently used in first-line MM therapy, and lenalidomide-based therapy was most common in second-line. Establishment and implementation challenges include regulatory and a range of operational issues. CONCLUSION: The APAC MRDR is providing 'real-world' data to participating sites, clinicians and policy-makers to explore factors influencing outcomes and survival, and to support high quality studies. It is already a valuable resource that will continue to grow and support research and clinical collaboration in MM and related diseases across the APAC region.

Opportunities for targeted therapies: trametinib as a therapeutic approach to canine oral squamous cell carcinomas.

Oral tumors are relatively common in dogs, and canine oral squamous cell carcinoma (COSCC) is the most prevalent oral malignancy of epithelial origin. COSCC is locally aggressive with up to 20% of patients showing regional or distant metastasis at the time of diagnosis. The treatment of choice most typically involves wide surgical excision. Although long-term remission is possible, treatments are associated with significant morbidity and can negatively impact functionality and quality of life. OSCCs have significant upregulation of the RAS-RAF-MEK-MAPK signaling axis, and we had previously hypothesized that small-molecule inhibitors that target RAS signaling might effectively inhibit tumor growth and progression. Here, we demonstrate that the MEK inhibitor trametinib, an FDA-approved drug for human cancers, significantly blocks the growth of several COSCC cell lines established from current patient tumor samples. We further show clinical evidence that the drug is able to cause significant tumor regression in some patients with spontaneously occurring COSCC. Given the limited treatment options available and the high rate of owner rejection of these offered options, these findings provide new hope that more acceptable treatment options may soon enter the veterinary clinic.

An International Survey of Extracorporeal Membrane Oxygenation Education and Credentialing Practices.

Background: The use of extracorporeal membrane oxygenation (ECMO) has grown rapidly over the past decades because of evolving indications, advances in circuit technology, and encouraging results from modern trials. Because ECMO is a complex and highly invasive therapy that requires a multidisciplinary team, optimal education, training, and credentialing remain a challenge. Objective: The primary objectives of this study were to investigate the prevalence and application of ECMO education and ECMO practitioner credentialing at ECMO centers globally. In addition, we explored differences among education and credentialing practices in relation to various ECMO center characteristics. Methods: We conducted an observational study of ECMO centers worldwide using a survey querying participants in two major domains: ECMO education and ECMO practitioner credentialing. Of note, the questionnaire included ECMO program characteristics, such as type and size of hospital and ECMO experience and volume, to explore the association with the two domains. Results: A total of 241 (32%) of the 732 identified ECMO centers responded to the survey, representing 41 countries across the globe. ECMO education was offered at 221 (92%) of the 241 centers. ECMO education was offered at 105 (98.0%) high-ECMO volume centers compared with 136 (87.5%) low-ECMO volume centers (P = 0.005). Credentialing was established at 101 (42%) of the 241 centers. Credentialing processes existed at 52 (49.5%) high-ECMO volume centers compared with 51 (37.5%) low-ECMO volume centers (P = 0.08) and 101 (49.3%) Extracorporeal Life Support Organization centers compared with 1 (2.7%) non-Extracorporeal Life Support Organization center (P < 0.001). Conclusion: We found significant variability in whether ECMO educational curricula are offered at ECMO centers. We also found fewer than half of the ECMO centers surveyed had established credentialing programs for ECMO practitioners. Future studies that assess variability in outcomes among centers with and without standardized educational and credentialing practices are needed.

Sexual Self Discrepancies, Sexual Satisfaction, and Relationship Satisfaction in a Cross-Sectional Sample of Women Who Experience Chronic Vaginal Pain during Sexual Intercourse.

One out of three women may suffer from chronic vaginal pain during intercourse, a complex health issue that leads to lasting psychological, sexual, emotional, and relational difficulties even after initial relief. Women who experience this pain condition may compare their sexual selves to the societal norm of being pain-free. Comparisons that do not align with one's actual sexual self result in sexual self-discrepancies and may cause emotional distress. Sexual self-discrepancies may hinder sexual and relationship satisfaction for women who experience chronic vaginal pain during sexual intercourse. This mixed-method study examined the sexual self-discrepancies women reported and the degree to which their sexual self-discrepancies were related to their sexual and relationship satisfaction. Results from this cross-sectional study showed that the majority of participants experienced sexual self-discrepancies and that they experienced a significant inverse correlation between sexual self-discrepancies and sexual satisfaction. In multivariate models, sex frequency was the strongest predictor of sexual satisfaction. There were no correlations between sexual self-discrepancies and relationship satisfaction. Future measurement research should examine the role of sex frequency in the experience of sexual satisfaction. Education on maximizing pleasure and minimizing pain may aid women to cope with the negative impact of pain.

Venipuncture Site Influences Blood-drop Volume in C57BL/6 Mice.

Many experiments require the collection of serial blood samples from mice. However, the size of mice limits the volume of blood that can be safely collected as a survival procedure. In IACUC protocols, investigators may report the amount of blood they collect from mice as a number of drops. Many institutions, including ours, use an anecdotal conversion factor (1drop of mouse blood = 25µL) to ensure that blood-collection volumes are compliant with institutional guidelines. To our knowledge, previous work has not experimentally determined the volume of a drop of mouse blood. In this 10-wk crossover experiment, 2 phlebotomists bled 30 C57BL/6J mice from 3 sites (facial, saphenous, and tail) using one or 2 different needle gauge sizes per site. Male and female mice were weighed weekly and divided among 5 groups (n = 6): left and right tail vein, left and right saphenous vein, and facial vein. A single blood drop from each site was weighed, and the volume of each drop was calculated using the average blood density determined from 8 mice terminally bled at the end of the study. Venipuncture site and side significantly influenced blood-drop weight and thus calculated volume. Facial vein puncture produced the largest drop volume (mean: 21.7µL), followed by the saphenous vein (mean: 9.97µL) and tail vein (mean: 4.96µL). Collection from the facial vein was associated with more hemorrhage and morbidity. Left-sided venipuncture was associated with slightly larger-volume blood drops, though the effect size of side was small. The results of this study may be useful in more accurately estimating blood loss via conversion of drops to volume. Our data indicate that blood collection from saphenous and tail veins minimizes blood loss relative to facial vein puncture and may optimize both serial collection of small-volume blood samples and animal welfare.

Designing a Web-Based Navigation Tool to Support Access to Youth Mental Health Services: Qualitative Study.

BACKGROUND: Many young people with mental health problems do not readily seek help or receive treatment and support. One way to address low help-seeking behavior is to improve access to information on mental health services and how to navigate the mental health system via a web-based tool. Seeking input from the end users (young people and parents or caregivers) on key features of the tool is imperative to ensure that it is relevant, engaging, and likely to meet their needs and expectations. OBJECTIVE: This study aims to investigate young person and parent or caregiver views on the design, content, functioning, and user experience of a web-based mental health navigation tool to support connection to mental health services for children and young people aged up to 25 years. METHODS: A total of 4 online focus groups were conducted: 2 with young people aged 16 years and older (total n=15) and 2 with parents or caregivers (total n=13). Focus groups were structured around a series of guiding questions to explore participants' views on content, features, user experience, and design of a mental health navigation website. Focus groups were audio recorded with detailed notes taken. In addition, 53 young people aged 16-25 years and 97 parents or caregivers completed an online survey, comprising closed- and open-ended questions; open-ended responses were included with the focus group data in the qualitative analysis. All qualitative data were analyzed using thematic analysis. RESULTS: A total of 2 topic areas and 7 themes were developed. The first topic area covered the types of information needs of young people and parents. Identified themes concerned the scope of the navigation website, as well as the provision of up-to-date and practical information on how to navigate the whole help-seeking process. The second topic area covered website features that would be beneficial and included the consideration of the website design; search engines; supported navigation; and forums, reviews, and user accounts. CONCLUSIONS: This study provides important insights into the navigation needs of young people and parents or caregivers in seeking mental health services. Key findings identified through this research have directly informed the development of MindMap, a web-based youth navigation tool providing a searchable database of local services, including a clear description, their location, and potential wait times. The website can be navigated independently or with support.

The photonics and optics workforce: unleashing the potential for greater industry growth-introduction to the feature issue.

This feature issue highlights specific photonics and optics workforce challenges, opportunities for industry support, and state-of-the-art-training methods.

DNA polymerase ε and δ variants drive mutagenesis in polypurine tracts in human tumors.

Alterations in the exonuclease domain of DNA polymerase ε cause ultramutated cancers. These cancers accumulate AGA>ATA transversions; however, their genomic features beyond the trinucleotide motifs are obscure. We analyze the extended DNA context of ultramutation using whole-exome sequencing data from 524 endometrial and 395 colorectal tumors. We find that G>T transversions in POLE-mutant tumors predominantly affect sequences containing at least six consecutive purines, with a striking preference for certain positions within polypurine tracts. Using this signature, we develop a machine-learning classifier to identify tumors with hitherto unknown POLE drivers and validate two drivers, POLE-E978G and POLE-S461L, by functional assays in yeast. Unlike other pathogenic variants, the E978G substitution affects the polymerase domain of Pol ε. We further show that tumors with POLD1 drivers share the extended signature of POLE ultramutation. These findings expand the understanding of ultramutation mechanisms and highlight peculiar mutagenic properties of polypurine tracts in the human genome.

A Qualitative Study of the Social Relationship Experiences Across the Life Course Among Black/African American Women Aging With HIV in the South.

ABSTRACT: Black/African American women continue to be disproportionately affected by HIV, facing multiple intersecting challenges that influence how they age and effectively manage their health. Supportive social relationships have been shown to help mitigate challenges and improve health in women with HIV, but little is known about Black/African American women's perceptions of social relationships. Guided by Life Course Theory, in-depth life history interviews were conducted with 18 Black/African American women aged 50+ years. In older adulthood, most important relationships among Black/African American women were with their adult children and grandchildren, intimate partners, God, and friends from the community. Factors that influenced relationships over time included: (a) a desire to build a community; (b) a need to empower oneself and give back; (c) yearning to engage the younger generation; and (d) battling HIV stigma. Older Black/African American women with HIV played a critical role in the education of the younger generation.

A deep neural network estimation of brain age is sensitive to cognitive impairment and decline.

The greatest known risk factor for Alzheimer's disease (AD) is age. While both normal aging and AD pathology involve structural changes in the brain, their trajectories of atrophy are not the same. Recent developments in artificial intelligence have encouraged studies to leverage neuroimaging-derived measures and deep learning approaches to predict brain age, which has shown promise as a sensitive biomarker in diagnosing and monitoring AD. However, prior efforts primarily involved structural magnetic resonance imaging and conventional diffusion MRI (dMRI) metrics without accounting for partial volume effects. To address this issue, we post-processed our dMRI scans with an advanced free-water (FW) correction technique to compute distinct FW-corrected fractional anisotropy (FAFWcorr) and FW maps that allow for the separation of tissue from fluid in a scan. We built 3 densely connected neural networks from FW-corrected dMRI, T1-weighted MRI, and combined FW+T1 features, respectively, to predict brain age. We then investigated the relationship of actual age and predicted brain ages with cognition. We found that all models accurately predicted actual age in cognitively unimpaired (CU) controls (FW: r=0.66, p=1.62x10-32; T1: r=0.61, p=1.45x10-26, FW+T1: r=0.77, p=6.48x10-50) and distinguished between CU and mild cognitive impairment participants (FW: p=0.006; T1: p=0.048; FW+T1: p=0.003), with FW+T1-derived age showing best performance. Additionally, all predicted brain age models were significantly associated with cross-sectional cognition (memory, FW: ß=-1.094, p=6.32x10-7; T1: ß=-1.331, p=6.52x10-7; FW+T1: ß=-1.476, p=2.53x10-10; executive function, FW: ß=-1.276, p=1.46x10-9; T1: ß=-1.337, p=2.52x10-7; FW+T1: ß=-1.850, p=3.85x10-17) and longitudinal cognition (memory, FW: ß=-0.091, p=4.62x10-11; T1: ß=-0.097, p=1.40x10-8; FW+T1: ß=-0.101, p=1.35x10-11; executive function, FW: ß=-0.125, p=1.20x10-10; T1: ß=-0.163, p=4.25x10-12; FW+T1: ß=-0.158, p=1.65x10-14). Our findings provide evidence that both T1-weighted MRI and dMRI measures improve brain age prediction and support predicted brain age as a sensitive biomarker of cognition and cognitive decline.

Real-world outcomes in relapsed refractory multiple myeloma patients exposed to three or more prior treatments: an analysis from the ANZ myeloma and related diseases registry.

BACKGROUND: There is no currently available standard of care for triple-class exposed, relapsed refractory myeloma (RRMM) patients in Australia. CARTITUDE-1 (CART-1) was a single-arm, phase 1b/2 study of 97 triple-class exposed RRMM patients, who received BCMA-CAR-T cell therapy with ciltacabtagene autocel. Overall response rate (ORR) was 98%. Median progression free survival (PFS) and overall survival (OS) had not been reached at a median follow-up of 28 months. METHODS: We performed a retrospective analysis on a cohort of CART-1 comparable RRMM patients participating in the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR), to compare outcomes in triple-class exposed MM patients treated with currently available therapies, in a real-world context. The CE-MRDR cohort (n = 28) fulfilled CARTITUDE-1 eligibility (CE) criteria: ≥3 lines of therapy (LOT) including an immunomodulatory agent, proteasome inhibitor and CD38-directed monoclonal antibody (CD38mAb) and Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0-2 at diagnosis. The modified-CE-MRDR (n = 132) received ≥3 LOT but may not have received a CD38mAb with an ECOG PS score of 3 (0-3). RESULTS: Responses to the first subsequent therapy after eligibility were poor - ORR was 23% and 0% with progressive disease (PD) reported in 61% and 36%, CE-MRDR and m-CE-MRDR respectively. Responses to the second subsequent therapy after eligibility were worse, ORR 0% and 31%, CE-MRDR and m-CE-MRDR respectively, with high rates of PD, particularly in CE-MRDR. Median OS was 5.4 versus 9.5 months, CE-MRDR versus m-CE-MRDR. CONCLUSIONS: This retrospective analysis confirms uniformly poor outcomes for Australian RRMM patients. There remains a critical need for greater accessibility to novel treatments, such as CAR-T, outside clinical trials.