The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer.

PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1,2, who were germline BRCA1 and BRCA2 wild type3. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)4, and secondary end points included event-free survival (EFS) and overall survival (OS)5. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 .

Effectiveness of population-based recovery actions for threatened southern mountain caribou.

Habitat loss is affecting many species, including the southern mountain caribou (Rangifer tarandus caribou) population in western North America. Over the last half century, this threatened caribou population's range and abundance have dramatically contracted. An integrated population model was used to analyze 51 years (1973-2023) of demographic data from 40 southern mountain caribou subpopulations to assess the effectiveness of population-based recovery actions at increasing population growth. Reducing potential limiting factors on threatened caribou populations offered a rare opportunity to identify the causes of decline and assess methods of recovery. Southern mountain caribou abundance declined by 51% between 1991 and 2023, and 37% of subpopulations were functionally extirpated. Wolf reduction was the only recovery action that consistently increased population growth when applied in isolation, and combinations of wolf reductions with maternal penning or supplemental feeding provided rapid growth but were applied to only four subpopulations. As of 2023, recovery actions have increased the abundance of southern mountain caribou by 52%, compared to a simulation with no interventions. When predation pressure was reduced, rapid population growth was observed, even under contemporary climate change and high levels of habitat loss. Unless predation is reduced, caribou subpopulations will continue to be extirpated well before habitat conservation and restoration can become effective.

CSF ferritin in the clinicopathological progression of Alzheimer's disease and associations with APOE and inflammation biomarkers.

BACKGROUND: A putative role for iron in driving Alzheimer's disease (AD) progression is complicated by previously reported associations with neuroinflammation, apolipoprotein E and AD proteinopathy. To establish how iron interacts with clinicopathological features of AD and at what disease stage iron influences cognitive outcomes, we investigated the association of cerebrospinal fluid (CSF) biomarkers of iron (ferritin), inflammation (acute phase response proteins) and apolipoproteins with pathological biomarkers (CSF Aß42/t-tau, p-tau181), clinical staging and longitudinal cognitive deterioration in subjects from the BioFINDER cohort, with replication of key results in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. METHODS: Ferritin, acute phase response proteins (n=9) and apolipoproteins (n=6) were measured in CSF samples from BioFINDER (n=1239; 4 years cognitive follow-up) participants stratified by cognitive status (cognitively unimpaired, mild cognitive impairment, AD) and for the presence of amyloid and tangle pathology using CSF Aß42/t-tau (A+) and p-tau181 (T+). The ferritin and apolipoprotein E associations were replicated in the ADNI (n=264) cohort. RESULTS: In both cohorts, ferritin and apoE were elevated in A-T+ and A+T+ subjects (16%-40%), but not clinical diagnosis. Other apolipoproteins and acute phase response proteins increased with clinical diagnosis, not pathology. CSF ferritin was positively associated with p-tau181, which was mediated by apolipoprotein E. An optimised threshold of ferritin predicted cognitive deterioration in mild cognitive impairment subjects in the BioFINDER cohort, especially those people classified as A-T- and A+T-. CONCLUSIONS: CSF markers of iron and neuroinflammation have distinct associations with disease stages, while iron may be more intimately associated with apolipoprotein E and tau pathology.

Intraoperative Multivessel Embolization Reduces Blood Loss and Transfusion Requirements Compared to Internal Iliac Artery Balloon Placement during Cesarean Hysterectomy for Placenta Accreta Spectrum.

PURPOSE: To evaluate the effectiveness and safety of prophylactic multivessel selective embolization (MVSE) compared to those of internal iliac artery occlusion balloon (IIABO) placement in patients undergoing cesarean hysterectomy for placenta accreta spectrum (PAS). MATERIALS AND METHODS: An institutional review board-approved retrospective series was conducted with consecutive patients with PAS at a single institution between 2010 and 2021. MVSE was performed in a hybrid operating room after cesarean section prior to hysterectomy. IIABO was performed with balloons placed into the bilateral internal iliac arteries, which were inflated during hysterectomy. Median blood loss, transfusion requirements, percentage of cases requiring transfusion, and adverse events were recorded. RESULTS: A total of 20 patients treated with embolization and 34 patients with balloon placement were included. Placenta percreta and previa were seen in 60% and 90% of patients, respectively. Median blood loss in the MVSE group was 713 mL (interquartile range [IQR], 475-1,000 mL) compared to 2,000 mL (IQR, 1,500-2,425 mL) in the IIABO group (P < .0001). The median total number of units of packed red blood cell transfusions (0 vs 2.5) and percentage of cases requiring a transfusion (20% vs 65%) were less in the MVSE group (P < .01). A median of 4 vessels (IQR, 3-9) were embolized during MVSE. No major adverse events or nontarget embolization consequences were observed. CONCLUSIONS: Prophylactic MVSE is a safe procedure that reduces operative blood loss and transfusion requirements compared to those of IIABO in patients undergoing cesarean hysterectomy for presumed higher-degree PAS.

Deep Learning Automated Background Phase Error Correction for Abdominopelvic 4D Flow MRI.

Background Four-dimensional (4D) flow MRI has the potential to provide hemodynamic insights for a variety of abdominopelvic vascular diseases, but its clinical utility is currently impaired by background phase error, which can be challenging to correct. Purpose To assess the feasibility of using deep learning to automatically perform image-based background phase error correction in 4D flow MRI and to compare its effectiveness relative to manual image-based correction. Materials and Methods A convenience sample of 139 abdominopelvic 4D flow MRI acquisitions performed between January 2016 and July 2020 was retrospectively collected. Manual phase error correction was performed using dedicated imaging software and served as the reference standard. After reserving 40 examinations for testing, the remaining examinations were randomly divided into training (86% [85 of 99]) and validation (14% [14 of 99]) data sets to train a multichannel three-dimensional U-Net convolutional neural network. Flow measurements were obtained for the infrarenal aorta, common iliac arteries, common iliac veins, and inferior vena cava. Statistical analyses included Pearson correlation, Bland-Altman analysis, and F tests with Bonferroni correction. Results A total of 139 patients (mean age, 47 years ± 14 [standard deviation]; 108 women) were included. Inflow-outflow correlation improved after manual correction (ρ = 0.94, P < .001) compared with that before correction (ρ = 0.50, P < .001). Automated correction showed similar results (ρ = 0.91, P < .001) and demonstrated very strong correlation with manual correction (ρ = 0.98, P < .001). Both correction methods reduced inflow-outflow variance, improving mean difference from -0.14 L/min (95% limits of agreement: -1.61, 1.32) (uncorrected) to 0.05 L/min (95% limits of agreement: -0.32, 0.42) (manually corrected) and 0.05 L/min (95% limits of agreement: -0.38, 0.49) (automatically corrected). There was no significant difference in inflow-outflow variance between manual and automated correction methods (P = .10). Conclusion Deep learning automated phase error correction reduced inflow-outflow bias and variance of volumetric flow measurements in four-dimensional flow MRI, achieving results comparable with manual image-based phase error correction. © RSNA, 2021 See also the editorial by Roldán-Alzate and Grist in this issue.

The Neuroinflammatory Acute Phase Response in Parkinsonian-Related Disorders.

BACKGROUND: Neuroinflammation is implicated in the pathophysiology of Parkinson's disease (PD) and related conditions, yet prior clinical biomarker data report mixed findings. OBJECTIVES: The aim was to measure a panel of neuroinflammatory acute phase response (APR) proteins in the cerebrospinal fluid (CSF) of participants with PD and related disorders. METHODS: Eleven APR proteins were measured in the CSF of 867 participants from the BioFINDER cohort who were healthy (612) or had a diagnosis of PD (155), multiple system atrophy (MSA) (26), progressive supranuclear palsy (PSP) (22), dementia with Lewy bodies (DLB) (23), or Parkinson's disease with dementia (PDD) (29). RESULTS: CSF APR proteins were mostly unchanged in PD, with only haptoglobin and α1-antitrypsin significantly elevated compared to controls. These proteins were variably increased in the other disorders. Certain protein components yielded unique signatures according to diagnosis: ferritin and transthyretin were selectively elevated in MSA and discriminated these patients from all others. Haptoglobin was selectively increased in PSP, discriminating this disease from MSA when used in combination with ferritin and transthyretin. This panel of proteins did not correlate well with severity of motor impairment in any disease category, but several (particularly ceruloplasmin and ferritin) were associated with memory performance (Mini-Mental State Examination) in patients with DLB and PDD. CONCLUSIONS: These findings provide new insights into inflammatory changes in PD and related disorders while also introducing biomarkers of potential clinical diagnostic utility. © 2022 International Parkinson and Movement Disorder Society.

Analysis of plasma proteins using 2D gels and novel fluorescent probes: in search of blood based biomarkers for Alzheimer's disease.

BACKGROUND: The Australian Imaging and Biomarker Lifestyle (AIBL) study of aging is designed to aid the discovery of biomarkers. The current study aimed to discover differentially expressed plasma proteins that could yield a blood-based screening tool for Alzheimer's disease. METHODS: The concentration of proteins in plasma covers a vast range of 12 orders of magnitude. Therefore, to search for medium to low abundant biomarkers and elucidate mechanisms of AD, we immuno-depleted the most abundant plasma proteins and pre-fractionated the remaining proteins by HPLC, prior to two-dimensional gel electrophoresis. The relative levels of approximately 3400 protein species resolved on the 2D gels were compared using in-gel differential analysis with spectrally resolved fluorescent protein detection dyes (Zdyes™). Here we report on analysis of pooled plasma samples from an initial screen of a sex-matched cohort of 72 probable AD patients and 72 healthy controls from the baseline time point of AIBL. RESULTS: We report significant changes in variants of apolipoprotein E, haptoglobin, α1 anti-trypsin, inter-α trypsin inhibitor, histidine-rich glycoprotein, and a protein of unknown identity. α1 anti-trypsin and α1 anti-chymotrypsin demonstrated plasma concentrations that were dependent on APOE ε4 allele dose. Our analysis also identified an association with the level of Vitamin D binding protein fragments and complement factor I with sex. We then conducted a preliminary validation study, on unique individual samples compared to the discovery cohort, using a targeted LC-MS/MS assay on a subset of discovered biomarkers. We found that targets that displayed a high degree of isoform specific changes in the 2D gels were not changed in the targeted MS assay which reports on the total level of the biomarker. CONCLUSIONS: This demonstrates that further development of mass spectrometry assays is needed to capture the isoform complexity that exists in theses biological samples. However, this study indicates that a peripheral protein signature has potential to aid in the characterization of AD.

Effect of Crystal Growth on the Thermodynamic Stability and Oxygen Reduction Reaction Activity of Cu-Pt Nanoparticles.

Thermodynamically stable (ordered) platinum-based bimetallic nanoparticle (NP) catalysts are auspicious candidates for catalyzing the oxygen reduction reaction (ORR) in fuel cells. Although the cubic (L12) and tetragonal (L10) ordered phases have been extensively studied, very little is known about the cubic (D7) thermally stable/ordered CuPt7 with regard to its synthesis at room temperature and ORR activity. The typical synthetic approach to the ordered phase (L12 and L10) has been by thermal annealing of the disordered phase in an inert atmosphere. We demonstrate that by coordinating Cu2+ and Pt4+ ions to amino groups in aqueous polyethyleneimine (PEI) (precursor solution), slow crystal growth by a UV-light assisted photoreduction can be used to achieve ordered CuPt7 NPs at room temperature. Slow crystal growth produces a relatively expanded lattice (7.766 Å) of CuPt7 and a lesser ORR activity via a four-electron transfer pathway. Conversely, fast crystal growth through a NaBH4 assisted chemical reduction produces a disordered CuPt phase at room temperature and a contracted lattice (3.809 Å) that enhances the ORR activity of CuPt via a two-electron transfer pathway. Our comparative observations of CuPt and CuPt7 support the observation that lattice contraction is critical in the ORR activity of Cu-Pt nanoalloys.

The Relationship Between Maxillary Growth and Speech in Children With a Unilateral Cleft Lip and Palate at 5 Years of Age.

OBJECTIVE: This study sought to investigate the association between maxillary growth and speech outcomes for children with a repaired unilateral cleft lip and palate (UCLP) at 5 years of age. PARTICIPANTS: In all, 521 children (180 females and 341 males) with a nonsyndromic complete UCLP, born between 2007 and 2012 in England, Wales, and Northern Ireland were included in this study. OUTCOME MEASURES: Maxillary growth was analyzed using dental models scored by the 5-Year-Olds' index, and perceptual speech analyses were scored by the Cleft Audit Protocol for Speech - Augmented rating. RESULTS: Forty-one percent of the children achieved good maxillary growth (scores 1 and 2 on 5-Year-Old' index). Fifty percent of the children achieved normal speech (achieving UK speech standard 1). Maxillary growth was not found to have an impact on speech outcome when described by the 3 UK National Cleft Lip and Palate Speech Audit Outcome Standards. Analysis according to individual speech parameters showed dentalizations to be less prevalent in children with good maxillary growth compared to fair and poor growth (P = .001). The remaining speech parameters within resonance, nasal airflow, and articulation categories were not significantly associated with maxillary growth. CONCLUSION: The findings from this study suggest that children with a history of complete UCLP, who have poor maxillary growth, are not at a higher risk of having major speech errors compared to children with good or fair maxillary growth at 5 years of age.

Placenta Accreta Spectrum Treatment With Intraoperative Multivessel Embolization: the PASTIME protocol.

BACKGROUND: Multidisciplinary care of placenta accreta spectrum cases improves pregnancy outcomes, but the specific components of such a multidisciplinary collaboration varies between institutions. As experience with placenta accreta spectrum increases, it is crucial to assess new surgical techniques and protocols to help improve maternal outcomes and to advocate for hospital resources. OBJECTIVE: This study aimed to assess a novel multidisciplinary protocol for the treatment of placenta accreta spectrum that comprises cesarean delivery, multivessel uterine embolization, and hysterectomy in a single procedure within a hybrid operative suite. STUDY DESIGN: This was a matched prepost study of placenta accreta spectrum cases managed before (2010-2017) and after implementation of the Placenta Accreta Spectrum Treatment With Intraoperative Multivessel Embolization protocol (2018-2021) at a tertiary medical center. Historical cases were managed with internal iliac artery balloon placement in selected cases with the decision to inflate the balloons intraoperatively at the discretion of the primary surgeon. Intraoperative Embolization cases were compared with historical cases in a 1:2 ratio matched on the basis of placenta accreta spectrum severity and surgical urgency. The primary outcome was a requirement for transfusion with packed red blood cells. Secondary outcomes included estimated surgical blood loss, operative and postoperative complications, procedural time, length of stay, and neonatal outcomes. RESULTS: A total of 15 Placenta Accreta Spectrum Treatment With Intraoperative Multivessel Embolization cases and 30 matched historical cases were included in the analysis. There were no demographic differences noted between the groups. A median (interquartile range) of 0 units (0-2 units) of packed red blood cells were transfused in the Intraoperative Embolization group compared with 2 units (0-4.5 units) in the historical group (P=.045); 5 of 15 (33.3%) Intraoperative Embolization cases required blood transfusions compared with 19 of 30 (63.3%) cases in the historical group (P=.11). The estimated blood loss was significantly less in the Intraoperative Embolization group with a median (interquartile range) of 750 mL (450-1050 mL) compared with 1750 mL (1050-2500 mL) in the historical group (P=.003). There were no cases requiring massive transfusion (≥10 red blood cell units in 24 hours) in the Intraoperative Embolization group compared with 5 of 30 (16.7%) cases in the historical group (P=.15). There were no intraoperative deaths from hemorrhagic shock using the Intraoperative Embolization protocol, whereas this occurred in 2 of the historical cases. The mean duration of the interventional radiology procedure was longer in the Intraoperative Embolization group (67.8 vs 34.1 minutes; P=.002). Intensive care unit admission and postpartum length of stay were similar, and surgical and postoperative complications were not significantly different between the groups. The gestational age and neonatal birthweights were similar; however, the neonatal length of stay was longer in the Intraoperative Embolization group (median duration, 32 days vs 15 days; P=.02) with a trend toward low Apgar scores. Incidence of arterial umbilical cord blood pH <7.2 and respiratory distress syndrome and intubation rates were not statistically different between the groups. CONCLUSION: A multidisciplinary pathway including a single-surgery protocol with multivessel uterine embolization is associated with a decrease in blood transfusion requirements and estimated blood loss with no increase in operative complications. The Placenta Accreta Spectrum Treatment With Intraoperative Multivessel Embolization protocol provides a definitive surgical method that warrants consideration by other centers specializing in placenta accreta spectrum treatment.