Validation of Prognostic and Predictive Models for Therapeutic Response in Patients Treated with [177Lu]Lu-PSMA-617 Versus Cabazitaxel for Metastatic Castration-resistant Prostate Cancer (TheraP): A Post Hoc Analysis from a Randomised, Open-label, Phase 2 Trial.

BACKGROUND: Prognostic models have been developed using data from a multicentre noncomparative study to forecast the likelihood of a 50% reduction in prostate-specific antigen (PSA50), longer prostate-specific antigen (PSA) progression-free survival (PFS), and longer overall survival (OS) in patients with metastatic castration-resistant prostate cancer receiving [177Lu]Lu-PSMA radioligand therapy. The predictive utility of the models to identify patients likely to benefit most from [177Lu]Lu-PSMA compared with standard chemotherapy has not been established. OBJECTIVE: To determine the predictive value of the models using data from the randomised, open-label, phase 2, TheraP trial (primary objective) and to evaluate the clinical net benefit of the PSA50 model (secondary objective). DESIGN, SETTING, AND PARTICIPANTS: All 200 patients were randomised in the TheraP trial to receive [177Lu]Lu-PSMA-617 (n = 99) or cabazitaxel (n = 101) between February 2018 and September 2019. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Predictive performance was investigated by testing whether the association between the modelled outcome classifications (favourable vs unfavourable outcome) was different for patients randomised to [177Lu]Lu-PSMA versus cabazitaxel. The clinical benefit of the PSA50 model was evaluated using a decision curve analysis. RESULTS AND LIMITATIONS: The probability of PSA50 in patients classified as having a favourable outcome was greater in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (odds ratio 6.36 [95% confidence interval {CI} 1.69-30.80] vs 0.96 [95% CI 0.32-3.05]; p = 0.038 for treatment-by-model interaction). The PSA50 rate in patients with a favourable outcome for [177Lu]Lu-PSMA-617 versus cabazitaxel was 62/88 (70%) versus 31/85 (36%). The decision curve analysis indicated that the use of the PSA50 model had a clinical net benefit when the probability of a PSA response was ≥30%. The predictive performance of the models for PSA PFS and OS was not established (treatment-by-model interaction: p = 0.36 and p = 0.41, respectively). CONCLUSIONS: A previously developed outcome classification model for PSA50 was demonstrated to be both predictive and prognostic for the outcome after [177Lu]Lu-PSMA-617 versus cabazitaxel, while the PSA PFS and OS models had purely prognostic value. The models may aid clinicians in defining strategies for patients with metastatic castration-resistant prostate cancer who failed first-line chemotherapy and are eligible for [177Lu]Lu-PSMA-617 and cabazitaxel. PATIENT SUMMARY: In this report, we validated previously developed statistical models that can predict a response to Lu-PSMA radioligand therapy in patients with advanced prostate cancer. We found that the statistical models can predict patient survival, and aid in determining whether Lu-PSMA therapy or cabazitaxel yields a higher probability to achieve a serum prostate-specific antigen response.

Overall survival with [177Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): secondary outcomes of a randomised, open-label, phase 2 trial.

BACKGROUND: The TheraP study reported improved prostate-specific antigen responses with lutetium-177 [177Lu]Lu-PSMA-617 versus cabazitaxel in men with metastatic castration-resistant prostate cancer progressing after docetaxel. In this Article, we report the secondary outcome of overall survival with mature follow-up, and an updated imaging biomarker analysis. We also report the outcomes of participants excluded due to ineligibility on gallium-68 [68Ga]Ga-PSMA-11 and 2-[18F]fluoro-2-deoxy-D-glucose (2-[18F]FDG) PET-CT. METHODS: TheraP was an open-label, randomised phase 2 trial at 11 centres in Australia. Eligible participants had metastatic castration-resistant prostate cancer progressing after docetaxel, and PET imaging with [68Ga]Ga-PSMA-11 and 2-[18F]FDG that showed prostate-specific membrane antigen (PSMA)-positive disease and no sites of metastatic disease with discordant 2-[18F]FDG-positive and PSMA-negative findings. Participants were randomly assigned (1:1) to treatment with [177Lu]Lu-PSMA-617 (every 6 weeks for a maximum of six cycles; starting at 8·5 GBq, decreasing by 0.5 GBq to 6·0 GBq for the sixth cycle) versus cabazitaxel (20 mg/m2 every 3 weeks, maximum of ten cycles). Overall survival was analysed by intention-to-treat and summarised as restricted mean survival time (RMST) to account for non-proportional hazards, with a 36-month restriction time corresponding to median follow-up. This trial is registered with ClinicalTrials.gov, NCT03392428, and is complete. FINDINGS: 291 men were registered from Feb 6, 2018, to Sept 3, 2019; after study imaging, 200 were eligible and randomly assigned to treatment with [177Lu]Lu-PSMA-617 (n=99) or cabazitaxel (n=101). After completing study treatment, 20 (20%) participants assigned to cabazitaxel and 32 (32%) assigned to [177Lu]Lu-PSMA-617 were subsequently treated with the alternative regimen. After a median follow-up of 35·7 months (IQR 31·1 to 39·2), 77 (78%) participants had died in the [177Lu]Lu-PSMA-617 group and 70 (69%) participants had died in the cabazitaxel group. Overall survival was similar among those assigned to [177Lu]Lu-PSMA-617 versus those assigned to cabazitaxel (RMST 19·1 months [95% CI 16·9 to 21·4] vs 19·6 months [17·4 to 21·8]; difference -0·5 months [95% CI -3·7 to 2·7]; p=0·77). No additional safety signals were identified with the longer follow-up in this analysis. 80 (27%) of 291 men who were registered after initial eligibility screening were excluded after [68Ga]Ga-PSMA-11 and 2-[18F]FDG PET. In the 61 of these men with follow-up available, RMST was 11·0 months (95% CI 9·0 to 13·1). INTERPRETATION: These results support the use of [177Lu]Lu-PSMA-617 as an alternative to cabazitaxel for PSMA-positive metastatic castration-resistant prostate cancer progressing after docetaxel. We did not find evidence that overall survival differed between the randomised groups. Median overall survival was shorter for men who were excluded because of low PSMA expression or 2-[18F]FDG-discordant disease. FUNDING: Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, It's a Bloke Thing, CAN4CANCER, and The Distinguished Gentleman's Ride.

Accuracy of oncologists' estimates of expected survival time in advanced cancer.

BACKGROUND: To evaluate the claim that oncologists overestimate expected survival time (EST) in advanced cancer. METHODS: We pooled 7 prospective studies in which observed survival time (OST) was compared with EST (median survival in a group of similar patients estimated at baseline by the treating oncologist). We hypothesized that EST would be well calibrated (approximately 50% of EST longer than OST) and imprecise (<30% of EST within 0.67 to 1.33 of OST), and that multiples of EST would provide well-calibrated scenarios for survival time: worst-case (approximately 10% of OST <1/4 of EST), typical (approximately 50% of OST within half to double EST), and best-case (approximately 10% of OST >3 times EST). Associations between baseline characteristics and calibration of EST were assessed. RESULTS: Characteristics of 1,211 patients: median age 66 years, male 61%, primary site lung (40%) and upper gastrointestinal (16%). The median OST was 8 months, and EST was 9 months. Oncologists' estimates of EST were well calibrated (50% longer than OST) and imprecise (28% within 0.67 to 1.33 of OST). Scenarios for survival time based on simple multiples of EST were well calibrated: 8% of patients had an OST less than 1/4 their EST (worst-case), 56% had an OST within half to double their EST (typical), and 11% had an OST greater than 3 times their EST (best-case). Calibration was independent of age, sex, and cancer type. CONCLUSIONS: Oncologists were no more likely to overestimate survival time than to underestimate it. Simple multiples of EST provide well-calibrated estimates of worst-case, typical, and best-case scenarios for survival.

The role of health demands, health resources, and adaptability in psychological strain and life satisfaction.

The present study harnessed job demands-resources theory to identify key predictors of psychological strain (feeling overwhelmed by one's problems) and life satisfaction among a sample of 1060 adults randomly selected from the Australian electoral roll. The investigation sought to ascertain: (a) the relative contribution of health demands (e.g., inadequate health treatment) and health resources (e.g., access to helpful health-related information) in predicting psychological strain and life satisfaction, (b) the extent to which a recently proposed personal resource-adaptability-explained variance in wellbeing beyond individuals' health demands and resources, and (c) the role of psychological strain in predicting life satisfaction in the context of these demands and resources. Applying structural equation modelling we found that contextual health demands predicted greater psychological strain, individual health resources and adaptability both predicted lower psychological strain and greater life satisfaction, and psychological strain predicted lower life satisfaction. Notably, the adverse effects of health demands reduced significantly when health resources and adaptability were entered into the modelling. Taken together, the findings offer support for a health demands-resources framework that may be applied to better support individuals to respond to the stressors in their lives and in turn boost their sense of subjective wellbeing.

Cerebral venous sinus thrombosis secondary to acute cytomegalovirus infection.

Background: Cerebral venous sinus thrombosis (CVST) is a potentially life-threatening disorder with a number of causes, including viral infections. Case presentation: A 25-year-old female patient presented with a non-specific febrile illness, headache and hepatitis. She was found to have right transverse sinus and cortical venous thrombosis in addition to acute systemic Cytomegalovirus (CMV) infection. She responded well to anticoagulation with warfarin for 6 months. CMV infection was treated conservatively. Conclusion: CVST is an increasingly prevalent condition often presenting with headache, focal neurological deficits and seizures. Despite extensive investigations, often no specific cause is found. CMV is a ubiquitous virus that can present with a non-specific febrile illness or a variety of organ dysfunction. CMV has been shown to be associated with predominantly venous thrombosis, most commonly lower limb deep venous thrombosis, pulmonary embolism and splanchnic vein thrombosis. The risk is highest in immunocompromised patients, though most patients are immunocompetent. There have been few reports of CVST related to CMV and all of these with a more tenuous link to acute CMV infection. Clinicians should be aware of this link, particularly in those who have CVST in the context of a febrile illness, or immunocompromised patients.

Nicotinamide for Skin-Cancer Chemoprevention in Transplant Recipients.

BACKGROUND: Immunosuppressed organ-transplant recipients have an increased incidence of, and mortality from, skin cancer. Nicotinamide (vitamin B3) enhances the repair of ultraviolet (UV) radiation-induced DNA damage, reduces the cutaneous immunosuppressive effects of UV radiation, and reduces the incidence of keratinocyte cancers (including squamous-cell and basal-cell carcinomas) and actinic keratoses among high-risk immunocompetent patients. Whether oral nicotinamide is useful for skin-cancer chemoprevention in organ-transplant recipients is unclear. METHODS: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, organ-transplant recipients who had had at least two keratinocyte cancers in the past 5 years to receive 500 mg of nicotinamide or placebo twice daily for 12 months. Participants were examined for skin lesions by dermatologists at 3-month intervals for 12 months. The primary end point was the number of new keratinocyte cancers during the 12-month intervention period. Secondary end points included the numbers of squamous-cell and basal-cell carcinomas during the 12-month intervention period, the number of actinic keratoses until 6 months after randomization, safety, and quality of life. RESULTS: A total of 158 participants were enrolled, with 79 assigned to the nicotinamide group and 79 to the placebo group. The trial was stopped early owing to poor recruitment. At 12 months, there were 207 new keratinocyte cancers in the nicotinamide group and 210 in the placebo group (rate ratio, 1.0; 95% confidence interval, 0.8 to 1.3; P = 0.96). No significant between-group differences in squamous-cell and basal-cell carcinoma counts, actinic keratosis counts, or quality-of-life scores were observed. Adverse events and changes in blood or urine laboratory variables were similar in the two groups. CONCLUSIONS: In this 12-month, placebo-controlled trial, oral nicotinamide therapy did not lead to lower numbers of keratinocyte cancers or actinic keratoses in immunosuppressed solid-organ transplant recipients. (Funded by the National Health and Medical Research Council; ONTRANS Australian New Zealand Clinical Trials Registry number, ACTRN12617000599370.).

Culture, Motivation, Self-Regulation, and the Impactful Work of Dennis M. McInerney.

This tribute celebrates the distinguished scholarship and extraordinary life of Dennis Michael McInerney, who passed away in Hong Kong on May 20th, 2022. It is a testimony of his impact on our professional and personal lives while highlighting the multitude and depth of his scholarly contributions. McInerney was one of those thinkers who invited us to reconsider how we conceptualize, assess, and apply scientific investigations in our teaching and learning practices. He authored and co-authored numerous widely used books and published numerous research articles in peer-refereed journals. During his remarkable career, McInerney dedicated a significant part to researching the problems associated with studying culture and uncovering how culture is a missing link in most motivation research. He believed there was a noteworthy need to conduct Indigenous educational research to understand the extent to which mainstream motivation theories apply to culturally diverse groups and stand up to cross-cultural testing scrutiny. McInerney's influence and impact will transcend future generations of research, given the gravity of his scholarly contributions.

Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial.

BACKGROUND: The interim analysis of the ENZAMET trial of testosterone suppression plus either enzalutamide or standard nonsteroidal antiandrogen therapy showed an early overall survival benefit with enzalutamide. Here, we report the planned primary overall survival analysis, with the aim of defining the benefit of enzalutamide treatment in different prognostic subgroups (synchronous and metachronous high-volume or low-volume disease) and in those who received concurrent docetaxel. METHODS: ENZAMET is an international, open-label, randomised, phase 3 trial conducted at 83 sites (including clinics, hospitals, and university centres) in Australia, Canada, Ireland, New Zealand, the UK, and the USA. Eligible participants were males aged 18 years or older with metastatic, hormone-sensitive prostate adenocarcinoma evident on CT or bone scanning with 99mTc and an Eastern Cooperative Oncology Group performance status score of 0-2. Participants were randomly assigned (1:1), using a centralised web-based system and stratified by volume of disease, planned use of concurrent docetaxel and bone antiresorptive therapy, comorbidities, and study site, to receive testosterone suppression plus oral enzalutamide (160 mg once per day) or a weaker standard oral non-steroidal antiandrogen (bicalutamide, nilutamide, or flutamide; control group) until clinical disease progression or prohibitive toxicity. Testosterone suppression was allowed up to 12 weeks before randomisation and for up to 24 months as adjuvant therapy. Concurrent docetaxel (75 mg/m2 intravenously) was allowed for up to six cycles once every 3 weeks, at the discretion of participants and physicians. The primary endpoint was overall survival in the intention-to-treat population. This planned analysis was triggered by reaching 470 deaths. This study is registered with ClinicalTrials.gov, NCT02446405, ANZCTR, ACTRN12614000110684, and EudraCT, 2014-003190-42. FINDINGS: Between March 31, 2014, and March 24, 2017, 1125 participants were randomly assigned to receive non-steroidal antiandrogen (n=562; control group) or enzalutamide (n=563). The median age was 69 years (IQR 63-74). This analysis was triggered on Jan 19, 2022, and an updated survival status identified a total of 476 (42%) deaths. After a median follow-up of 68 months (IQR 67-69), the median overall survival was not reached (hazard ratio 0·70 [95% CI 0·58-0·84]; p<0·0001), with 5-year overall survival of 57% (0·53-0·61) in the control group and 67% (0·63-0·70) in the enzalutamide group. Overall survival benefits with enzalutamide were consistent across predefined prognostic subgroups and planned use of concurrent docetaxel. The most common grade 3-4 adverse events were febrile neutropenia associated with docetaxel use (33 [6%] of 558 in the control group vs 37 [6%] of 563 in the enzalutamide group), fatigue (four [1%] vs 33 [6%]), and hypertension (31 [6%] vs 59 [10%]). The incidence of grade 1-3 memory impairment was 25 (4%) versus 75 (13%). No deaths were attributed to study treatment. INTERPRETATION: The addition of enzalutamide to standard of care showed sustained improvement in overall survival for patients with metastatic hormone-sensitive prostate cancer and should be considered as a treatment option for eligible patients. FUNDING: Astellas Pharma.

INTEGRATE II: randomised phase III controlled trials of regorafenib containing regimens versus standard of care in refractory Advanced Gastro-Oesophageal Cancer (AGOC): a study by the Australasian Gastro-Intestinal Trials Group (AGITG).

BACKGROUND: Advanced gastro-oesophageal cancer (AGOC) carries a poor prognosis. No standard of care treatment options are available after first and second-line therapies. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor targeting angiogenic, stromal, and oncogenic receptor tyrosine kinases. Regorafenib 160 mg daily prolonged progression free survival compared to placebo (INTEGRATE, phase 2). Regorafenib 80 mg daily in combination with nivolumab 3 mg/kg showed promising objective response rates (REGONIVO). METHODS/DESIGN: INTEGRATE II (INTEGRATE IIa and IIb) platform comprises two international phase III randomised controlled trials (RCT) with 2:1 randomisation in favor of experimental intervention. INTEGRATE IIa (double-blind) compares regorafenib 160 mg daily on days 1 to 21 of each 28-day cycle to placebo. INTEGRATE IIb (open label) compares REGONIVO, regorafenib 90 mg days 1 to 21 in combination with intravenous nivolumab 240 mg days 1 and 15 each 28-day cycle with investigator's choice of chemotherapy (control). Treatment continues until disease progression or intolerable adverse events as per protocol. Eligible participants include adults with AGOC who have failed two or more lines of treatment. Stratification is by location of tumour (INTEGRATE IIa only), geographic region, prior VEGF inhibitor and prior immunotherapy use (INTEGRATE IIb only). Primary endpoint is overall survival. Secondary endpoints are progression free survival, objective response rate, quality of life, and safety. Tertiary/correlative objectives include biomarker and pharmacokinetic evaluation. DISCUSSION: INTEGRATE II provides a platform to evaluate the clinical utility of regorafenib alone, as well as regorafenib in combination with nivolumab in treatment of participants with refractory AGOC. TRIAL REGISTRATION: INTEGRATE IIa prospectively registered 1 April 2016 Australia New Zealand Clinical Trial Registry: ACTRN12616000420448 (ClinicalTrials.gov NCT02773524). INTEGRATE IIb prospectively registered 10 May 2021 ClinicalTrials.gov: NCT04879368.

The potential of biophysiology for understanding motivation, engagement and learning experiences.

BACKGROUND AND AIMS: Integrative models applied to human learning and performance emphasize the joint operation of biological, psychological, social, and educational processes to fully understand human functioning. Educational psychology researchers have typically emphasized psycho-educational and psycho-social factors in motivation, engagement and learning, but do not often consider the biophysiological factors. RESULTS: This Editorial and Special Issue advances current understanding on the role of biophysiological factors and processes in students' and teachers' motivation, engagement, and learning experiences, by showcasing recent educational research that included biophysiological measures and methods. CONCLUSIONS: As we discuss, conducting integrative biophysiological and psycho-educational research has potential to derive vital substantive, methodological, and applied insights that provide a rigorous basis for more effective educational theory, research, and practice.

School principals' mental health and well-being under threat: A longitudinal analysis of workplace demands, resources, burnout, and well-being.

Schools are critical organisational settings, and school principals face extreme stress levels. However, there are few large-scale, longitudinal studies of demands and resources that drive principals' health and well-being. Using the Job Demands-Resources (JD-R) framework, we evaluated longitudinal reciprocal effects over 3 years relating to job demands, job resources (resilience), job-related outcomes (burnout and job satisfaction), and personal outcomes (happiness and physical health) for a nationally representative sample of 3683 Australian school principals. Prior demands and resources led to small changes in subsequent outcomes, beneficial effects of resources, and adverse effects of demands, particularly for job-related outcomes. Furthermore, we also found reverse-reciprocal effects, prior outcomes (burnout and job satisfaction) influencing subsequent job characteristics. However, in response to substantively and theoretically important research questions, we found no support for Yerkes-Dodson Law (nonlinear effects of demands) or Nietzsche effects and inoculation effects (that which does not kill you, makes you stronger; manageable levels of demands build resilience). Relating our study to new and evolving issues in JD-R research, we offer limitations of our research-and JD-R theory and research more generally-and directions for further research in this essentially unstudied application of JD-R to school principals' mental health and well-being.

University students in COVID-19 lockdown: The role of adaptability and fluid reasoning in supporting their academic motivation and engagement.

This study drew on Job Demands-Resources theory and data from 500 Australian university students to investigate the role of COVID-related lockdown, perceived adaptability, and fluid reasoning in students' self-efficacy-and the role of these factors in students' engagement and disengagement. Lockdown was associated with higher disengagement; perceived adaptability was associated with higher self-efficacy; and both perceived adaptability and fluid reasoning were significantly and positively associated with engagement. Self-efficacy significantly mediated the relationship between perceived adaptability and engagement and disengagement, while moderation tests revealed that fluid reasoning yielded a significant positive role for the self-efficacy of students in lockdown. These findings shed light on factors during COVID-19 that are implicated in students' academic development and provide direction for psycho-educational interventions.

The Prognostic Value of Posttreatment 68Ga-PSMA-11 PET/CT and 18F-FDG PET/CT in Metastatic Castration-Resistant Prostate Cancer Treated with 177Lu-PSMA-617 and NOX66 in a Phase I/II Trial (LuPIN).

177Lu-PSMA-617 therapy has shown high prostate-specific antigen (PSA) response rates in men with metastatic castration-resistant prostate cancer. However, early treatment resistance is common. This LuPIN substudy aimed to determine the prognostic value of posttreatment quantitative PET for PSA progression-free survival (PFS) and overall survival (OS) with 177Lu-PSMA-617 therapy. Methods: Fifty-six men with progressive metastatic castration-resistant prostate cancer were enrolled in the LuPIN trial and received up to 6 doses of 177Lu-PSMA-617 and a radiation sensitizer (NOX66). 68Ga-PSMA-11 and 18F-FDG PET/CT, diagnostic CT, and bone scanning were performed at study entry and exit. Quantitative analysis tracked change in total tumor volume (TTV) and SUV. Univariable and multivariable analyses were conducted to examine the association of change in TTV (continuous and >30%), SUVmax, PSA, and radiographic progression with PSA PFS and OS. Results: All men (37/56) who underwent both screening and posttreatment molecular imaging were analyzed; 70% (26/37) had a PSA response of more than 50%. Median PSA PFS was 8.6 mo, and median OS was 22 mo. Clinical progression had occurred at trial exit in 54% (20/37). In response to treatment, a reduced PSMA SUVmax was demonstrated in 95% (35/37) and a reduced PSMA TTV in 68% (25/37). An increase in PSMA TTV by at least 30% was associated with worse OS (median, 10.2 vs. 23.6 mo; P = 0.002). Change in PSMA SUVmax was not associated with PSA PFS or OS. 18F-FDG SUVmax was reduced in 51% (18/35) and 18F-FDG TTV in 67% (22/35). An increased 18F-FDG SUVmax was associated with worse OS (median, 20.7 vs. 25.7 mo; P < 0.01). An 18F-FDG TTV increase by more than 30% was associated with a short PSA PFS (median, 3.5 vs. 8.6 mo; P < 0.001) but not OS. Both PSA and radiographic progression were associated with shorter OS (median, 14.5 vs. 25.7 mo [P < 0.001] and 12.2 vs. 23.6 mo [P = 0.002]). On multivariable analysis, only increased PSMA TTV and PSA progression remained independently prognostic of OS (hazard ratio, 5.1 [95% CI, 1.5-17.1; P = 0.008] and 3.5 [95% CI, 1.1-10.9; P = 0.03], respectively). Conclusion: Change in quantitative PSMA TTV has strong potential as a prognostic biomarker with 177Lu-PSMA-617 therapy, independent of 18F-FDG PET parameters, PSA, or radiographic progression. Further research into the value of posttreatment PET as an imaging biomarker is warranted.

Evaluation of 177Lu-PSMA-617 SPECT/CT Quantitation as a Response Biomarker Within a Prospective 177Lu-PSMA-617 and NOX66 Combination Trial (LuPIN).

177Lu-PSMA-617 is an effective and novel treatment in metastatic castration-resistant prostate cancer (mCRPC). Our ability to assess response rates and therefore efficacy may be improved using predictive tools. This study investigated the predictive value of serial 177Lu-PSMA-617 SPECT/CT (177Lu SPECT) imaging in monitoring treatment response. Methods: Fifty-six men with progressive mCRPC previously treated with chemotherapy and novel androgen signaling inhibitor were enrolled into the LuPIN trial and received up to 6 doses of 177Lu-PSMA-617 and a radiation sensitizer (3-(4-hydroxyphenyl)-2H-1-benzopyran-7-ol [NOX66]). 68Ga-PSMA-11 and 18F-FDG PET/CT were performed at study entry and exit, and 177Lu SPECT from vertex to mid thighs was performed 24 h after each treatment. SPECT quantitative analysis was undertaken at cycles 1 (baseline) and 3 (week 12) of treatment. Results: Thirty-two of the 56 men had analyzable serial 177Lu SPECT imaging at both cycle 1 and cycle 3. In this subgroup, median prostate-specific antigen (PSA) progression-free survival (PFS) was 6.3 mo (95% CI, 5-10 mo) and median overall survival was 12.3 mo (95% CI, 12-24 mo). The PSA 50% response rate was 63% (20/32). 177Lu SPECT total tumor volume (SPECT TTV) was reduced in 68% (22/32; median, -0.20 m3 [95% CI, -1.4 to -0.001]) and increased in 31% (10/32; median, 0.36 [95% CI, 0.1-1.4]). Any increase in SPECT TTV was associated with shorter PSA PFS (hazard ratio, 4.1 [95% CI, 1.5-11.2]; P = 0.006). An increase of 30% or more in SPECT TTV was also associated with a shorter PSA PFS (hazard ratio, 3.3 [95% CI, 1.3-8.6]; P =0.02). Tumoral SUVmax was reduced in 91% (29/32) and SUVmean in 84% (27/32); neither was associated with PSA PFS or overall survival outcomes. PSA progression by week 12 was also associated with a shorter PSA PFS (hazard ratio, 26.5 [95% CI, 5.4-131]). In the patients with SPECT TTV progression at week 12, 50% (5/10) had no concurrent PSA progression (median PSA PFS, 4.5 mo [95% CI, 2.8-5.6 mo]), and 5 of 10 men had both PSA and SPECT TTV progression at week 12 (median PSA PFS, 2.8 mo [95% CI, 1.8-3.7 mo]). Conclusion: Increasing SPECT TTV on quantitative 177Lu SPECT predicts a short PFS and may play a future role as an imaging response biomarker.

University Students' Motivation and Engagement During the COVID-19 Pandemic: The Roles of Lockdown, Isolation, and Remote and Hybrid Learning.

This investigation comprised two studies that sought to identify the role of COVID-related disruptions in Australian university students' academic motivation and engagement. Study 1 involved a dataset of 500 university students and examined the links between COVID-19 pandemic disruptions (remote and hybrid learning modes, lockdown, isolation) and students' adaptive (e.g., planning and monitoring) and maladaptive (e.g., disengagement) dimensions of the Motivation and Engagement Scale (MES). Study 2 compared the mean motivation and engagement of Study 1 participants with mean levels from four published pre-COVID-19 Australian studies (N = 55, N = 233, N = 420, N = 941 university students) that also used the MES. Study 1 showed that lockdown and isolation (and not remote/hybrid learning) were associated with problematic motivation and engagement-with lockdown and isolation effects particularly noteworthy for maladaptive motivation and engagement. Study 2 showed that relative to the four pre-COVID-19 samples, the COVID-19 pandemic sample experienced difficulties with motivation and engagement, and again particularly so on maladaptive dimensions.

Disentangling motivation and engagement: Exploring the role of effort in promoting greater conceptual and methodological clarity.

Conflation over motivation and engagement has historically impeded research and practice. One reason for this is because definition and measurement have often been too general or diffuse-especially in the case of engagement. Recently conceptual advances aimed at disentangling facets of engagement and motivation have highlighted a need for better psychometric precision-particularly in the case of engagement. To the extent that engagement is inadequately assessed, motivation research involving engagement continues to be hampered. The present study investigates multidimensional effort (a specific facet of engagement) and how it relates to motivation. In particular, we examine the associations between specific positive and negative motivation factors and dimensions of effort, thereby shedding further insight into how different types of motivation interplay with different types of engagement. Drawing on data from a sample of 946 Australian high school students in 59 mathematics classrooms at five schools, this study hypothesized a tripartite model of academic effort in terms of operative, cognitive, and social-emotional dimensions. A novel nine-item self-report Effort Scale measuring each of the three factors was developed and tested for internal and external validity-including its relationship with multidimensional motivation. Multilevel confirmatory factor analyses were conducted to test the factor structure and validity of multidimensional effort. Additionally, doubly-latent multilevel structural equation models were conducted to explore the hypothesized motivation → engagement (effort) process, and the role of student- and classroom-level background attributes as predictors of both motivation and effort. Results supported the hypothesized model of tripartite effort and its distinctiveness from motivation, and showed that key dimensions of motivation predicted effort at student- and classroom-levels. This study provides implications and suggestions for future motivation research and theorizing by (1) establishing evidence for the validity of a novel engagement framework (multidimensional effort), and (2) supporting future measurement and practice in academic engagement juxtaposed with multidimensional motivation-critical for better understanding engagement, and motivation itself.

Influences of renal insufficiency and ischemia on mitochondrial bioenergetics and limb dysfunction in a novel murine iliac arteriovenous fistula model.

Objective: Hand disability after hemodialysis access surgery has been common yet has remained poorly understood. Arteriovenous fistula (AVF) hemodynamic perturbations have not reliably correlated with the observed measures of hand function. Chronic kidney disease (CKD) is known to precipitate myopathy; however, the interactive influences of renal insufficiency and ischemia on limb outcomes have remained unknown. We hypothesized that CKD would contribute to access-related hand dysfunction via altered mitochondrial bioenergetics. Using a novel murine AVF model, we sought to characterize the skeletal muscle outcomes in mice with and without renal insufficiency. Methods: Male, 8-week-old C57BL/6J mice were fed either an adenine-supplemented diet to induce renal insufficiency (CKD) or a casein-based control chow (CON). After 2 weeks of dietary intervention, the mice were randomly assigned to undergo iliac AVF surgery (n = 12/group) or a sham operation (n = 5/group). Measurements of aortoiliac hemodynamics, hindlimb perfusion, and hindlimb motor function were collected for 2 weeks. The mice were sacrificed on postoperative day 14 to assess skeletal muscle histopathologic features and mitochondrial function. To assess the late outcome trends, 20 additional mice had undergone CKD induction and sham (n = 5) or AVF (n = 15) surgery and followed up for 6 weeks postoperatively before sacrifice. Results: The adenine-fed mice had had a significantly reduced glomerular filtration rate and elevated blood urea nitrogen, confirming the presence of CKD. The sham mice had a 100% survival rate and AVF cohorts an 82.1% survival rate with an 84.4% AVF patency rate. The aorta and inferior vena cava velocity measurements and the vessel diameter had increased after AVF creation (P < .0001 vs sham). The AVF groups had had a 78.4% deficit in paw perfusion compared with the contralateral limb after surgery (P < .0001 vs sham). Mitochondrial function was influenced by the presence of CKD. The respiratory capacity of the CKD-sham mice (8443 ± 1509 pmol/s/mg at maximal energy demand) was impaired compared with that of the CON-sham mice (12,870 ± 1203 pmol/s/mg; P = .0001). However, this difference was muted after AVF creation (CKD-AVF, 4478 ± 3685 pmol/s/mg; CON-AVF, 5407 ± 3582 pmol/s/mg; P = .198). The AVF cohorts had had impairments in grip strength (vs sham; P < .0001) and gait (vs sham; P = .012). However, the presence of CKD did not significantly alter the measurements of gross muscle function. The paw perfusion deficits had persisted 6 weeks postoperatively for the AVF mice (P < .0001 vs sham); however, the myopathy had resolved (grip strength, P = .092 vs sham; mitochondrial respiration, P = .108 vs sham). Conclusions: CKD and AVF-induced distal limb ischemia both impaired skeletal muscle mitochondrial function. Renal insufficiency was associated with a baseline myopathy that was exacerbated by the acute ischemic injury resulting from AVF creation. However, ischemia was the primary driver of the observed phenotype of gross motor impairment. This model reliably reproduced the local and systemic influences that contribute to access-related hand dysfunction and provides a platform for further mechanistic and therapeutic investigation.