Patterns of Treatment Failure in Primary Central Nervous System Lymphoma.

OBJECTIVES: Progression of PCNSL remains a challenge with salvage therapies, including the risk of substantial morbidity and mortality. We report patterns of first tumor progression to inform opportunities for improvement. METHODS: This is an institutional retrospective review from 2002 to 2021 of 95 consecutive patients with pathologically confirmed PCNSL, of whom 29 experienced progressive disease. Kaplan-Meier method, log-rank test, and Cox proportional hazard models are used to characterize associations of patient, tumor, and treatment variables with LC, PFS, and patterns of first failure. RESULTS: Most patients were below 65 years old (62%) with KPS >70 (64%) and negative CSF cytology (70%). In 70 patients with MRIs, the median tumor volume was 12.6 mL (range: 0.5 to 67.8 mL). After a median follow-up of 11 months, 1-year PFS was 48% and 1-year LC was 80%. Of the 29 patients with progression, 24% were distant only, 17% were distant and local, and 59% were local only. On MVA, LC was associated with age (HR: 1.08/y, P =0.02), KPS (HR: 0.10, P =0.02), completion of >6 cycles of HD-MTX (HR: 0.10, P <0.01), and use of intrathecal chemotherapy (HR: 0.03, P <0.01). On UVA, local only first failure trended to be increased with >14 mL tumors (OR: 5.06, P =0.08) with 1-year LC 83% (<14 mL) versus 64% (>14mL). There were no significant associations with LC and WBRT ( P =0.37), Rituximab ( P =0.12), or attempted gross total resection ( P =0.72). CONCLUSIONS: Our findings reaffirm the importance of systemic and intrathecal therapies for local control in PCNSL. However, bulky tumors trend to fail locally, warranting further investigation about the role of local therapies or systemic therapy intensification.

FIB-4 as a screening and disease monitoring method in pre-fibrotic stages of metabolic dysfunction-associated fatty liver disease (MASLD).

AIMS: Guidelines emphasize screening high-risk patients for metabolic dysfunction-associated steatotic liver disease (MASLD) with a calculated FIB-4 score for therapy to reverse fibrosis. We aimed to determine whether FIB-4 can effectively screen and monitor changes in steatohepatitis (MASH). METHODS: Data were retrieved from the NIDDK-CR R4R central repository, of the CRN/PIVENS (pioglitazone vs vitamin E vs placebo) trial of adult patients without diabetes mellitus and with MASLD. RESULTS: 220 patients with MASLD had alanine transaminase (ALT), aspartate aminotransferase (AST) and platelet count, to calculate FIB-4, and repeat liver biopsies for histological MASLD activity scores (NAS). Compared to NAS score of 2, Fib-4 was higher at NAS 5) (p = 0.03), and NAS score of 6 (p = 0.02). FIB-4 correlated with cellular ballooning (r = 0.309, p < 0.001). Levels of ALT (ANOVA, p = 0.016) and AST (ANOVA p = 0.0008) were associated with NAS. NAS improved with pioglitazone by 39 %, p < 0.001 and with vitamin E by 36 %, p < 0.001. Pioglitazone and vitamin E both improved histological sub-scores for steatosis, and inflammation, without statistical changes in fibrosis grade. Changes in FIB-4 correlated with changes in NAS (r = 0.237, p < 0.001). CONCLUSIONS: In this post hoc analysis, changes in FIB-4 were associated with changes of steatohepatitis. Medication known to treat steatohepatitis, may be considered, before the onset of advanced fibrosis.

Association of the Achondroplasia Foramen Magnum Score and intraoperative neuromonitoring.

INTRODUCTION: Foramen magnum stenosis in achondroplasia carries a risk of sudden death. A proportion of these patients benefit from foramen magnum decompression (FMD). The Achondroplasia Foramen Magnum Score (AFMS) was developed to stratify those most at risk. We hypothesise that this score may be reflected in neurophysiological findings. METHODS: Patients with achondroplasia who had undergone FMD (n=20) were retrospectively grouped into AFMS 2, 3 and 4. Amplitude from tibialis anterior (TA) and the percentage change in somatosensory evoked potential (SSEP) latency after FMD were reported. RESULTS: Baseline motor evoked potential amplitudes for patients with AFMS=4 were significantly lower left (p=0.0017 and p=0.02 for right and left TA, respectively) compared with AFMS grades 2 and 3. Median reduction (% change) in SSEP latency (ms) after surgery was not significantly different in any of the patients. CONCLUSIONS: This short report cross-references AFMS to intraoperative neuromonitoring. Baseline amplitudes were noticeably lower in the most severe AFMS group. This observation supports the notion that AFMS can help risk stratify patients and aid in surgical selection.

Reliability and validity of rapid assessment tools for measuring 24-hour movement behaviours in children aged 0-5 years: the Movement Behaviour Questionnaire Baby (MBQ-B) and child (MBQ-C).

BACKGROUND: The development of validated "fit-for-purpose" rapid assessment tools to measure 24-hour movement behaviours in children aged 0-5 years is a research priority. This study evaluated the test-retest reliability and concurrent validity of the open-ended and closed-ended versions of the Movement Behaviour Questionnaire for baby (MBQ-B) and child (MBQ-C). METHODS: 300 parent-child dyads completed the 10-day study protocol (MBQ-B: N = 85; MBQ-C: N = 215). To assess validity, children wore an accelerometer on the non-dominant wrist (ActiGraph GT3X+) for 7 days and parents completed 2 × 24-hour time use diaries (TUDs) recording screen time and sleep on two separate days. For babies (i.e., not yet walking), parents completed 2 × 24-hour TUDs recording tummy time, active play, restrained time, screen time, and sleep on days 2 and 5 of the 7-day monitoring period. To assess test-retest reliability, parents were randomised to complete either the open- or closed-ended versions of the MBQ on day 7 and on day 10. Test-retest intraclass correlation coefficients (ICC's) were calculated using generalized linear mixed models and validity was assessed via Spearman correlations. RESULTS: Test-retest reliability for the MBQ-B was good to excellent with ICC's ranging from 0.80 to 0.94 and 0.71-0.93 for the open- and closed-ended versions, respectively. For both versions, significant positive correlations were observed between 24-hour diary and MBQ-B reported tummy time, active play, restrained time, screen time, and sleep (rho = 0.39-0.87). Test-retest reliability for the MBQ-C was moderate to excellent with ICC's ranging from 0.68 to 0.98 and 0.44-0.97 for the open- and closed-ended versions, respectively. For both the open- and closed-ended versions, significant positive correlations were observed between 24-hour diary and MBQ-C reported screen time and sleep (rho = 0.44-0.86); and between MBQ-C reported and device-measured time in total activity and energetic play (rho = 0.27-0.42). CONCLUSIONS: The MBQ-B and MBQ-C are valid and reliable rapid assessment tools for assessing 24-hour movement behaviours in infants, toddlers, and pre-schoolers. Both the open- and closed-ended versions of the MBQ are suitable for research conducted for policy and practice purposes, including the evaluation of scaled-up early obesity prevention programs.

Physical Activity-Related Practices and Psychosocial Factors of Childcare Educators: A Latent Profile Analysis.

Limited research investigates early childhood education and care (ECEC) educators' involvement in promoting physical activity. The aim was to identify distinct profiles based on physical activity-related practices and psychosocial factors in ECEC educators and examine how they relate to the amount of time allocated to children's physical activity. A secondary analysis of educator-reported survey data from the Play Active study was undertaken. Educators (n = 532) reported on four practices and four psychosocial subscales adapted from the Environment and Policy Evaluation and Observation relating to the provision of physical activity in childcare. Latent profile analysis was used to identify distinct groups of educators based on their practices and psychosocial factors. Logistic regression analysed associations between latent profiles and educator-reported time provided for children's physical activity. Five profiles of educators' physical activity-related practices and psychosocial factors were identified. Profiles with higher practice scores also had higher psychosocial scores. Educators in profiles characterised by higher scores had greater odds of meeting the best practice guidelines for daily time allocated to children for total physical activity and energetic play. This study highlights interventions which address multiple educator behaviour change determinants to improve children's physical activity in childcare.

Maternal physical activity and sitting time and its association with placental morphology and blood flow during gestation: Findings from the Queensland Family Cohort study.

OBJECTIVES: Antenatal exercise is associated with placental morphological alterations, however research in this area is limited. Given the emphasis on the beneficial effects of antenatal exercise, it is important to understand its effect on placental function and the relationship to foetal development. The aim of this study was to investigate the association between physical activity, sitting time, and placental outcomes measured during gestation. DESIGN: Prospective cohort study. METHODS: Pregnant women in the Queensland Family Cohort study self-reported physical activity at 24 and 36 weeks of gestation (n = 203) and were categorised into physical activity volume groups of nil-low (0-<500 metabolic equivalent of task·minutes/week), moderate (500-<1000 metabolic equivalent of task·minutes/week), or high-volume activity (≥1000 metabolic equivalent of task·minutes/week). Participants reported average daily sitting time, whereby excessive sitting time was considered as ≥8h/day. Placental stiffness, thickness, and uteroplacental blood flow resistance were measured by ultrasound imaging at each timepoint. RESULTS: Physical activity volume was not associated with changes to placental morphometrics or uteroplacental blood flow resistance at 24 or 36 weeks of gestation. Excessive sitting time at 36 weeks was associated with greater placental stiffness (p = 0.046), and a lower umbilical artery pulsatility index (p = 0.001). CONCLUSIONS: Placental tissue stiffness and umbilical artery resistance were altered in late gestation with higher maternal sitting time but not with physical activity volume. Overall, excessive sitting time may be a risk for suboptimal placental function and could be an important focus for antenatal care.

Markerless motion capture provides accurate predictions of ground reaction forces across a range of movement tasks.

Measuring or estimating the forces acting on the human body during movement is critical for determining the biomechanical aspects relating to injury, disease and healthy ageing. In this study we examined whether quantifying whole-body motion (segmental accelerations) using a commercial markerless motion capture system could accurately predict three-dimensional ground reaction force during a diverse range of human movements: walking, running, jumping and cutting. We synchronously recorded 3D ground reaction forces (force instrumented treadmill or in-ground plates) with high-resolution video from eight cameras that were spatially calibrated relative to a common coordinate system. We used a commercially available software to reconstruct whole body motion, along with a geometric skeletal model to calculate the acceleration of each segment and hence the whole-body centre of mass and ground reaction force across each movement task. The average root mean square difference (RMSD) across all three dimensions and all tasks was 0.75 N/kg, with the maximum average RMSD being 1.85 N/kg for running vertical force (7.89 % of maximum). There was very strong agreement between peak forces across tasks, with R2 values indicating that the markerless prediction algorithm was able to predict approximately 95-99 % of the variance in peak force across all axes and movements. The results were comparable to previous reports using whole-body marker-based approaches and hence this provides strong proof-of-principle evidence that markerless motion capture can be used to predict ground reaction forces and therefore potentially assess movement kinetics with limited requirements for participant preparation.

A great way to bring up health behaviour topics at playgroup: a qualitative evaluation of the Healthy Conversations @ Playgroup program.

BACKGROUND: The early years is a critical stage to establish optimal nutrition and movement behaviours. Community playgroups are a relaxed environment for parents with a focus on social connection and supporting parents in their role as 'First Teachers'. Playgroups are therefore an opportunistic setting to promote health behaviours in the early years. To support parents with young children around healthy lifestyle behaviours, the Healthy Conversations @ Playgroup program was delivered in urban and regional areas, across three Australian jurisdictions between 2021-2023. OBJECTIVE: This qualitative evaluation aimed to understand how the Healthy Conversations @ Playgroup program was experienced by parents, playgroup coordinators and peer facilitators. DESIGN: Semi-structured virtual interviews and focus groups were conducted with parents, playgroup coordinators (i.e., person responsible for coordinating the playgroup) and peer facilitators (i.e., trained facilitator for the program) that participated in the Healthy Conversations @ Playgroup study. Transcripts were analysed following a thematic analysis approach. RESULTS: Twenty-eight playgroup parents, coordinators or peer facilitators participated in one of 8 focus groups or 5 interviews. Four themes were developed: Program strengths and challenges; Setting strengths and challenges; Factors that impact program delivery; Participant's suggestions for future program delivery. CONCLUSIONS: The Healthy Conversations @ Playgroup program was valued by parents, providing validation and normalisation of parenting practices, and fostering a shared experience of parenting. Playgroups are a convenient setting for families to attend. The dynamic and distracting nature of the playgroup setting were carefully considered when designing the program. Strategies to further enhance program engagement could include use of coordinator or parent champions, tailored delivery, and extending the reach to other family members. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12621000055808, registered 22 January 2021, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380890.

Neonatal seizures during extra corporeal membrane oxygenation support.

To evaluate EEG monitoring during neonatal ECMO and to identify any correlations between seizure detection to abnormal neuroimaging. Eight-year, service evaluation of neonates who received at least one continuous EEG (cEEG) whilst on ECMO at Great Ormond Street Hospital. Pearson's chi-square test and multivariate logistic regression analysis were used to assess clinical and EEG variables association with seizures and neuroimaging findings. Fifty-seven neonates were studied; 57 cEEG recordings were reviewed. The incidence of seizures was 33% (19/57); of these 74% (14/19) were electrographic-only. The incidence of status epilepticus was 42%, (8/19 with 6 neonates having electrographic-only status and 2 electro-clinical status. Seizures were detected within an hour of recording in 84%, (16/19). The overall mortality rate was 39% (22/57). Seizure detection was strongly associated with female gender (OR 4.8, 95% CI: 1.1-20.4, p = 0.03), abnormal EEG background activity (OR 2.8, 95% CI: 1.1-7.4, p = 0.03) and abnormal EEG focal features (OR 23.6, 95% CI: 5.4-103.9, p = 0.001). There was a strong association between the presence of seizures and abnormal neuroimaging findings (OR 10.9, 95% CI: 2.8-41.9, p = 0.001). Neonates were highly likely to have abnormal neuroimaging findings in the presence of severely abnormal background EEG (OR 9.5, 95% CI 1.7-52.02, p = 0.01) and focal EEG abnormalities (OR 6.35, 95% CI 1.97-20.5, p = 0.002)Conclusion: The study highlights the importance of cEEG in neonates undergoing ECMO. An association between seizure detection and abnormal neuroimaging findings was described. What is Known: • Patients on ECMO are at a higher risk of seiures. • Continuous EEG monitoring is recommended by the ACNS for high risk and ECMO patients. What is New: • In this cohort, neonates with sezirues were 11 times more likely of having abnromal neuroimaging findings. • Neonates with burst suppressed or suppressed EEG background were 9.5 times more likely to have abnormal neuroimaging findings. What does this study add? • This study reports a 33% incidence of neonatal seizures during ECMO. • Neonates with seizures were 11 times more likely to have an abnormal brain scan. • The study captures the real-time approach of EEG monitoring. • Recommended cEEG monitoring should last at least 24 h for ECMO patients. • This is the first study to assess this in neonates only.

Free drug and ROS-responsive nanoparticle delivery of synergistic doxorubicin and olaparib combinations to triple negative breast cancer models.

Combinations of the topoisomerase II inhibitor doxorubicin and the poly (ADP-ribose) polymerase inhibitor olaparib offer potential drug-drug synergy for the treatment of triple negative breast cancers (TNBC). In this study we performed in vitro screening of combinations of these drugs, administered directly or encapsulated within polymer nanoparticles, in both 2D and in 3D spheroid models of breast cancer. A variety of assays were used to evaluate drug potency, and calculations of combination index (CI) values indicated that synergistic effects of drug combinations occurred in a molar-ratio dependent manner. It is suggested that the mechanisms of synergy were related to enhancement of DNA damage as shown by the level of double-strand DNA breaks, and mechanisms of antagonism associated with mitochondrial mediated cell survival, as indicated by reactive oxygen species (ROS) generation. Enhanced drug delivery and potency was observed with nanoparticle formulations, with a greater extent of doxorubicin localised to cell nuclei as evidenced by microscopy, and higher cytotoxicity at the same time points compared to free drugs. Together, the work presented identifies specific combinations of doxorubicin and olaparib which were most effective in a panel of TNBC cell lines, explores the mechanisms by which these combined agents might act, and shows that formulation of these drug combinations into polymeric nanoparticles at specific ratios conserves synergistic action and enhanced potency in vitro compared to the free drugs.

Goal-directed therapeutic exercise for paediatric posterior fossa brain tumour survivors: a qualitative analysis of experiences.

PURPOSE: To explore child and parent experiences of a 12-week goal-directed therapeutic exercise intervention in paediatric posterior fossa brain tumours survivors and to identify features of the program that influenced program adherence and acceptability. METHODS: Eleven interviews were conducted; five parent-child dyads (mothers = 83%) and one parent only (mean child age = 10.6 ± 3.0 years; 83% male). Posterior fossa brain tumour survivors, who participated in a weekly goal-directed exercise program for 12 weeks, completed semi-structured interviews to discuss their experience of the program. An inductive content analysis was undertaken. Interviews were transcribed, imported into NVivo and independently coded by two reviewers. Code and content categories were iteratively discussed and refined. RESULTS: Five content categories were generated: (1) perceived improvements, (2) program logistics, (3) activity selection, (4) connection with the therapist and (5) options for technology. All participants valued the tailored exercise program and described improvements in movement competence. Children and their parents discussed preferring home- and community-based locations and favoured face-to-face delivery. Occasionally, parents reported difficulty completing the home program due to low child motivation or family time restrictions. Multiple families suggested an interactive digital application would be an effective delivery channel for the supplemental home-based program. CONCLUSION: A goal-directed exercise program delivered at home and in community-based locations was considered valuable and helpful for improving movement competence in paediatric survivors of posterior fossa brain tumour. TRIAL REGISTRATION: ACTRN12619000841178 June 12, 2019.

Longitudinal effects of dog ownership, dog acquisition, and dog loss on children's movement behaviours: findings from the PLAYCE cohort study.

INTRODUCTION: Regular physical activity is important for children's physical and mental health, yet many children do not achieve recommended amounts of physical activity. Dog ownership has been associated with increased physical activity in children, however, there have been no longitudinal studies examining this relationship. This study used data from the Play Spaces and Environments for Children's Physical Activity (PLAYCE) cohort study to examine the longitudinal effects of dog ownership status on children's movement behaviours. METHODS: Change in dog ownership from preschool (wave 1, age 2-5) to fulltime school (wave 2, age 5-7) was used as a natural experiment with four distinct dog ownership groups: continuing non-dog owners (n = 307), continuing dog owners (n = 204), dog acquired (n = 58), and dog loss (n = 31; total n = 600). Daily movement behaviours, including physical activity, sedentary time, sleep, and screen time, were measured using accelerometry and parent-report surveys. Differences between groups over time and by sex were tested using linear mixed effects regression models. RESULTS: Girls who acquired a dog increased their light intensity activities and games by 52.0 min/day (95%CI 7.9, 96.0) and girls who lost a dog decreased their light intensity activities and games by 62.1 min/day (95%CI -119.3, -4.9) compared to no change among non-dog owners. Girls and boys who acquired a dog increased their unstructured physical activity by 6.8 (95%CI 3.2, 10.3) and 7.1 (95%CI 3.9, 10.3) occasions/week, compared to no changes among non-dog owners. Girls and boys who lost a dog reduced their unstructured physical activity by 10.2 (95%CI -15.0, -5.3) and 7.7 (95%CI -12.0, -3.5) occasions/week. Girls who lost a dog decreased their total physical activity by 46.3 min/day (95%CI -107.5, 14.8) compared to no change among non-dog owners. Continuing dog ownership was typically not associated with movement behaviours. Dog ownership group was not associated with changes in sleep and had mixed associations with screen time. CONCLUSION: The positive influence of dog ownership on children's physical activity begins in early childhood and differs by child sex. Further research should examine the specific contributions dog-facilitated physical activity makes to children's overall physical activity, including the intensity and duration of dog walking and play.

Construct Validity of the Both Hands Assessment Using Wrist-Worn Accelerometers.

AIM: The aim of this study was to evaluate the construct validity of the Both Hands Assessment (BoHA) using activity of the upper limbs as detected by accelerometry in children with bilateral cerebral palsy (CP). METHODS: Observational study of children with CP (n = 44, n = 27 boys, aged 9.1 ± 1.6 years; Manual Ability Classification Scale I: n = 15, II: n = 22, III: n = 7) completing a BoHA assessment while wearing a triaxial accelerometer on each wrist. BoHA Each-Hand sub-scores, BoHA percentage difference between hands, BoHA Units, mean activity for each hand, mean activity asymmetry index and total mean activity were calculated. Linear regressions were used to analyze associations between measures. RESULTS: There were significant, positive associations between BoHA Units and total mean activity (B = 0.86, 95%CI: 0.32, 1.40), BoHA Percentage difference between hands and mean activity asymmetry index (B = 0.95, 95%CI: 0.75,1.15), and BoHA Each-Hand sub-score and mean activity for the non-dominant hand (B = 1.71, 95%CI: 1.16, 2.28), but not the dominant hand (B = 0.50, 95%CI: -0.45, 1.45). CONCLUSIONS: This study provides further evidence for the construct validity of the BoHA as a measure of upper limb performance. Wearable wrist sensors such as accelerometers capture and quantify gross upper limb movement in children with CP but cannot measure fine finger movements captured by the BoHA. CLINICAL TRIALS REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN12616001488493 and ACTRN12618000164291).

Stroke Prevention by Antihyperglycemic Drugs in Type 2 Diabetes Mellitus.

OBJECTIVES: The American Heart Association/American Stroke Association and the American Association of Clinical Endocrinology provided guidelines for patients with transient ischemic attacks or strokes (TIA/stroke) and diabetes mellitus with the use of glucose-lowering agents (GLA) effective in preventing major adverse cardiovascular events (MACE). This review evaluated GLA for specific differences in TIA/stroke prevention. METHODS: Previous reviews and meta-analyses were evaluated for outcomes of MACE, cardiovascular death (CVD), hospitalization for heart failure, and TIA/stroke. The GLA were glucagon-like peptide 1-receptor agonists (GLP-1RA, 6-trials, n = 46 541), sodium-glucose transport 2 inhibitors (SGLT2i, 5-trials, n = 46 959), insulin-providing regimens (IP, 4-trials, n = 26 223), and thiazolidinediones (TZD, 1-trial, n = 5238). RESULTS: There were reductions in MACE for each class. Relative risk (rr) reductions for TIA/stroke were found with GLP-1RA (rr = 0.840, 95% CI: 0.759, 0.936, P =.001) but not with SGLT2i, IP, or TZD. Cardiovascular deaths were decreased with GLP-1RA (rr = 0.873, CI: 0.804, 0.947, P =.001) and SGLT2i (rr = 0.835, CI: 0.706, 0.987, P =.034), but not with TZD or IP. Hospitalizations for heart failure were decreased only with SGLT2i (rr = 0.699, CI: 0.626, 0.781, P <.001). Increased CVD correlated with aggressive lowering of A1c (r = -0.611, P =.012) and showed a trend with the relative risk of hypoglycemia (r = 0.447, P =.08). For GLP-1RA, there was no increase in hypoglycemia and a direct correlation with a decreased rr for stroke with decreases in A1c (r = 0.917, P =.010). CONCLUSION: Improvements in A1c with GLP-1RA were associated with stroke prevention in patients with diabetes and with TIA or stroke. Reductions in cardiovascular mortality include therapy with GLP-1RA and SGLT2i. Aggressive lowering of A1c, however, was associated with increased CVD.

The effect of antenatal isoniazid preventive therapy on birth outcomes in Western Kenya.

BACKGROUND: Pregnant women living with HIV (WLHIV) are at high risk for TB. There are limited data to inform whether TB preventive therapy is safe in pregnancy.METHODS: We completed a retrospective study of antenatal and birth records of mother-infant dyads at two health care facilities in Kisumu, Kenya. Among pregnant WLHIV, we assessed the relationship of antenatal isoniazid preventive therapy (IPT) with birth outcomes (preterm birth, low birth weight [LBW], congenital anomalies, and perinatal death).RESULTS: Of 576 mother-infant pairs, most women were on antiretroviral therapy (574, 99.7%) with viral suppression (518, 89.9%) and one-quarter had IPT exposure during pregnancy (152, 26.4%). The prevalence of preterm birth was lower among women with antenatal IPT exposure (21% vs. 30%; P = 0.03). LBW, congenital anomaly and perinatal death were not associated with antenatal IPT; however, we observed a trend toward fewer composite poor birth outcomes among women taking antenatal IPT (26% vs 33%; P = 0.08). Controlling for maternal age and viral load, IPT use during pregnancy was associated with lower odds of preterm birth (aOR 0.62, 95% CI 0.40-0.98; P = 0.04).CONCLUSION: In a programmatic setting in Western Kenya, IPT use was not associated with adverse birth outcomes.

Unravelling transcriptomic complexity in breast cancer through modulation of DARPP-32 expression and signalling pathways.

DARPP-32 is a key regulator of protein-phosphatase-1 (PP-1) and protein kinase A (PKA), with its function dependent upon its phosphorylation state. We previously identified DKK1 and GRB7 as genes with linked expression using Artificial Neural Network (ANN) analysis; here, we determine protein expression in a large cohort of early-stage breast cancer patients. Low levels of DARPP-32 Threonine-34 phosphorylation and DKK1 expression were significantly associated with poor patient prognosis, while low levels of GRB7 expression were linked to better survival outcomes. To gain insight into mechanisms underlying these associations, we analysed the transcriptome of T47D breast cancer cells following DARPP-32 knockdown. We identified 202 differentially expressed transcripts and observed that some overlapped with genes implicated in the ANN analysis, including PTK7, TRAF5, and KLK6, amongst others. Furthermore, we found that treatment of DARPP-32 knockdown cells with 17ß-estradiol or PKA inhibitor fragment (6-22) amide led to the differential expression of 193 and 181 transcripts respectively. These results underscore the importance of DARPP-32, a central molecular switch, and its downstream targets, DKK1 and GRB7 in breast cancer. The discovery of common genes identified by a combined patient/cell line transcriptomic approach provides insights into the molecular mechanisms underlying differential breast cancer prognosis and highlights potential targets for therapeutic intervention.

Rural libraries implementing walking groups or walking groups plus civic engagement for walkability in rural communities: a comparative effectiveness trial study protocol.

BACKGROUND: Rural residents generally lack adequate physical activity to benefit health and reduce disparities in chronic diseases, such as cardiovascular disease and certain cancers. The Socioecological Model describes physical activity as involving a dynamic and reciprocal interaction between individual, social, and community factors. Community group-based walking programs and civic engagement interventions aimed at enhancing physical activity have been successful in rural communities but have not targeted all three socioecological levels. Public libraries can act as innovative public health partners in rural communities. However, challenges remain because rural libraries often lack the capacity to implement evidence-based health promotion programming. The goals of this study are (1) build the capacity for rural libraries to implement evidence-based health promotion programs, (2) compare changes in physical activity between a group-based walking program and a combined group-based walking and civic engagement program with rural residents, and (3) conduct an implementation evaluation. METHODS: We will conduct a comparative effectiveness study of a group-based walking (standard approach) versus a group-based walking plus civic engagement program (combined approach) aimed at enhancing walkability to increase physical activity among rural adults. Key mediators between the program effects and change in outcomes will also be identified. Finally, we will evaluate program implementation, conduct a cost effectiveness evaluation, and use a positive deviance analysis to understand experiences of high and low changers on key outcomes. Twenty towns will be matched and randomized to one of the two conditions and our aim is to enroll a total of 350-400 rural residents (15-20 per town). Study outcomes will be assessed at baseline, and 6, 12, and 24 months. DISCUSSION: This study will build the capacity of rural libraries to implement evidence-based walking programs as well as other health promotion programs in their communities. The study results will answer questions regarding the relative effectiveness and cost effectiveness of two multilevel physical activity interventions targeting rural communities. We will learn what works and how these multilevel interventions can be implemented in rural populations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05677906.

High BMP7 expression is associated with poor prognosis in ovarian cancer.

Bone Morphogenetic Protein 7 (BMP7) is an extracellular signalling protein that belongs to the transforming growth factor-ß (TGF- ß) superfamily. Previous transcriptomic data suggested that BMP7 expression may be disrupted in ovarian carcinoma and may play an important role in the aggressiveness of the disease. However, the protein expression in patient tumours has not been well studied. The current study aimed to assess BMP7 protein expression in a large cohort of ovarian carcinoma patient tumour samples to establish its associations with different clinical endpoints. Ovarian carcinoma tissue samples from 575 patients who underwent surgery for different subtypes of ovarian cancer were used. BMP7 protein expression was analysed by immunohistochemistry using tissue microarray and full face tumour sections. High BMP7 expression is associated with aggressive ovarian cancer clinicopathological variables including advanced FIGO stage, high grade, residual disease and poor overall survival. Elevated cytoplasmic and nuclear BMP7 expression was significantly associated with advanced FIGO stage, high tumour grade, presence of residual tumours and high-grade serous carcinomas (p = 0.001, 0.005, 0.004, <0.001 and p < 0.001, <0.001, 0.002, 0.001 respectively). Increased cytoplasmic and nuclear BMP7 expression was also significantly associated with an adverse overall survival (p = 0.001 and 0.046 respectively). The study highlights the potential of BMP7 as a prognostic tool and as a potential novel target for ovarian cancer therapies to limit disease progression.

Cognitive Testing of Items Measuring Movement Behaviours in Young Children Aged Zero to Five Years: Development of the Movement Behaviour Questionnaires for -Baby (MBQ-B) and -Child (MBQ-C).

This paper describes the cognitive interview phase of the development of two brief surveys, the Movement Behaviour Questionnaire-Baby (MBQ-B) and Movement Behaviour Questionnaire-Child (MBQ-C), which measure the duration of physical activity, screen time, and sleep of children aged 0-5 years. The aims were (1) review the format, content, and clarity of questionnaire items and response options, (2) understand how parents retrieve, encode, and formulate responses when asked about their child's movement behaviours, and (3) identify potential sources of response error and make appropriate modifications. Interviews with parents of children aged 0-5 years were conducted using concurrent think-aloud techniques and probing questions. Parents reviewed the MBQ-B and/or MBQ-C depending on the developmental stage of their child(ren). Twenty-nine interviews were conducted with 20 parents, over four iterative rounds. Participants recalled usual family routines and rules when estimating the duration/frequency of behaviours. To estimate active play, parents referred to the child's daily routine considering wake and bedtimes, naps, and mealtimes. Participants were influenced by the examples provided, being unable to interpret these as exemplars only. Decomposing general items into specific questions with examples was well received. Use of numeracy skills when estimating duration was evident. Interviews informed revisions to item wording, examples, and recall prompts, which will be taken forward into the MBQ-B and MBQ-C validation studies. Utilising cognitive interviewing can enhance confidence that questionnaire items are correctly interpreted and understood by participants.

Tumor microenvironment in a minipig model of spinal cord glioma.

BACKGROUND: Spinal cord glioma (SCG) is considered an orphan disease that lacks effective treatment options with margins that are surgically inaccessible and an overall paucity of literature on the topic. The tumor microenvironment is a critical factor to consider in treatment and modeling design, especially with respect to the unresectable tumor edge. Recently, our group developed a high-grade spinal cord glioma (SCG) model in Göttingen minipigs. METHODS: Immunofluorescence and ELISA were performed to explore the microenvironmental features and inflammation cytokines in this minipig SCG model. Protein carbonyl assay and GSH/GSSG assay were analyzed in the core and edge lesions in the minipig SCG model. The primary core and edge cells proliferation rate were shown in vitro, and the xenograft model in vivo. RESULTS: We identified an elevated Ki-67 proliferative index, vascular and pericyte markers, CD31 and desmin in the tumor edge as compared to the tumor core. In addition, we found that the tumor edge demonstrated increased pro-inflammatory and gliomagenic cytokines including TNF-α, IL-1ß, and IL-6. Furthermore, the mediation of oxidative stress is upregulated in the tumor edge. Hypoxic markers had statistically significant increased staining in the tumor core, but were notably still present in the tumor edge. The edge cells cultures derived from SCG biopsy also demonstrated an increased proliferative rate compared to core cell cultures in a xenotransplantation model. CONCLUSIONS: Our study demonstrates heterogeneity in microenvironmental features in our minipig model of high-grade SCG, with a phenotype at the edge showing increased oxidative stress, proliferation, inflammatory cytokines, neovascularization, and decreased but present staining for hypoxic markers. These findings support the utility of this model as a means for investigating therapeutic approaches targeting the more aggressive and surgically unresectable tumor border.