Machine learning analysis of a large set of homopolymers to predict glass transition temperatures.

Glass transition temperature of polymers, Tg, is an important thermophysical property, which sometimes can be difficult to measure experimentally. In this regard, data-driven machine learning approaches are important alternatives to assess Tg values, in a high-throughput way. In this study, a large dataset of more than 900 polymers with reported glass transition temperature (Tg) was assembled from various public sources in order to develop a predictive model depicting the structure-property relationships. The collected dataset was curated, explored via cluster analysis, and then split into training and test sets for validation purposes and then polymer structures characterized by molecular descriptors. To find the models, several machine learning techniques, including multiple linear regression (MLR), k-nearest neighbor (k-NN), support vector machine (SVM), random forest (RF), gaussian processes for regression (GPR), and multi-layer perceptron (MLP) were explored. As result, a model with the subset of 15 descriptors accurately predicting the glass transition temperatures was developed. The electronic effect indices were determined to be important properties that positively contribute to the Tg values. The SVM-based model showed the best performance with determination coefficients (R2) of 0.813 and 0.770, for training and test sets, respectively. Also, the SVM model showed the lowest estimation error, RMSE = 0.062. In addition, the developed structure-property model was implemented as a web app to be used as an online computational tool to design and evaluate new homopolymers with desired glass transition profiles.

Competing for Pixels: A Self-play Algorithm for Weakly-supervised Semantic Segmentation.

Weakly-supervised semantic segmentation (WSSS) methods, reliant on image-level labels indicating object presence, lack explicit correspondence between labels and regions of interest (ROIs), posing a significant challenge. Despite this, WSSS methods have attracted attention due to their much lower annotation costs compared to fully-supervised segmentation. Leveraging reinforcement learning (RL) self-play, we propose a novel WSSS method that gamifies image segmentation of a ROI. We formulate segmentation as a competition between two agents that compete to select ROI-containing patches until exhaustion of all such patches. The score at each time-step, used to compute the reward for agent training, represents likelihood of object presence within the selection, determined by an object presence detector pre-trained using only image-level binary classification labels of object presence. Additionally, we propose a game termination condition that can be called by either side upon exhaustion of all ROI-containing patches, followed by the selection of a final patch from each. Upon termination, the agent is incentivised if ROI-containing patches are exhausted or disincentivised if a ROI-containing patch is found by the competitor. This competitive setup ensures minimisation of over- or under-segmentation, a common problem with WSSS methods. Extensive experimentation across four datasets demonstrates significant performance improvements over recent state-of-the-art methods. Code: https://github.com/s-sd/spurl/tree/main/wss.

Open Bankart Repair with Subscapularis Split.

Background: Anterior shoulder dislocations are a common injury, especially in the young, active, male population1. Soft-tissue treatment options for shoulder instability include arthroscopic or open Bankart repair, with open Bankart repair historically having lower rates of recurrence and reoperation, faster return to activity2-4, and a similar quality of life compared with arthroscopic repair5. More recent literature has suggested similar recurrence rates between arthroscopic and open procedures6. However, open Bankart repair may be indicated in cases of recurrent instability, especially if the patient participates in high-risk sports, because open repair can provide more capsular shift through the use of extra-capsular knots7. Performing a subscapularis split decreases the likelihood of subscapularis tendon avulsion following subscapularis tendon tenotomy and subsequent repair, as has been described in the literature8. Description: Indications for open Bankart repair include failure of arthroscopic Bankart repair, multiple dislocations, with subcritical bone loss. This surgical technique is performed via the deltopectoral approach. The subscapularis tendon is exposed and "spared" by splitting the fibers with use of a longitudinal incision between the upper 2/3 and lower 1/3 of the subscapularis. We begin the split medially near the myotendinous junction. Because the subscapularis becomes increasingly difficult to separate from the capsule as it tracks laterally, a RAY-TEC sponge is utilized to bluntly dissect. A T-shaped laterally based capsulotomy is made to expose the glenohumeral joint. The vertical aspect is made first, followed by the horizontal aspect from lateral to medial, extending to the labrum. A Fukuda retractor is placed through the split to hold the humeral head laterally. The labrum is elevated, and the glenoid is prepared with rasp. Then labrum is repaired with knotted suture anchors until it is secure. One anchor is utilized for each "hour" of the clock face, with a minimum of 3 anchors. The anchors are placed on the articular margin of the glenoid. Sutures are passed from the anchor through the capsule and tied outside the capsule. The capsulotomy is then repaired with use of a suture. The suture is utilized to pull the inferior portion superiorly. The inferior portion is taken superiorly, and the superior leaflet is imbricated over the top. Finally, an examination is performed to ensure that the humeral head can be translated to but not over the anterior and posterior glenoid rims. No repair of the subscapularis tendon insertion is required. The incision is closed with deep dermal and subcuticular suture. Alternatives: Nonoperative treatment options include rotator cuff and periscapular strengthening or immobilization. Operative treatment options include open Bankart repair with subscapularis tenotomy and repair, arthroscopic Bankart repair, or bone block augmentation procedures. Rationale: This procedure is different from the alternative treatments in that it is an open procedure, which allows for a more robust repair because the capsule can be shifted and doubled over, leading to the described decreased recurrence and reoperation rates. Open Bankart repair is better suited for large lesions that would be difficult to repair via arthroscopy. This procedure differs from other open Bankart techniques because the subscapularis is split rather than tenotomized, which removes the need to repair the tendon and decreases the rate of avulsion of the subscapularis tendon repair. Finally, this procedure is less invasive than the Latarjet procedure because it does not require osseous osteotomies and fixation. Expected Outcomes: This procedure provides adequate capsular shift and visualization of the Bankart lesion without the increased risk of postoperative subscapularis tendon injury. Important Tips: If the subscapularis split alone does not provide adequate visualization, portions of the subscapularis tendon can be released from the lesser tuberosity.The location and origin of the upper and lower subscapular nerves can have variable courses, which could theoretically put them at risk for iatrogenic injury; however, studies have shown this subscapularis split technique to be safe from and prevent denervation of the muscle. Acronyms and Abbreviations: GBL = glenoid bone lossEUA = examination under anesthesiaMRI = magnetic resonance imagingHSL = Hill-Sachs lesionAHCA = anterior humeral circumflex artery.

Comparing Access to Engaging Hill-Sachs Lesions Between the Modified Posterior Deltoid Split Approach and Standard Deltopectoral Approach for Bone Grafting.

Background: Hill-Sachs lesions are common after shoulder instability, and treatment options vary but include remplissage or implantation of structural bone graft. Large Hill-Sachs lesions not addressed by remplissage are challenging to manage and may frequently require an open surgical approach for bone filling treatment options. The optimal approach to maximize visualization of the humeral head during these procedures remains unclear. Purpose/Hypothesis: The purpose of this study was to compare the area of the humeral head accessed using a modified posterior deltoid split approach versus a standard deltopectoral approach without surgical dislocation, with particular attention to access of engaging Hill-Sachs lesions for the purpose of bone grafting in the setting of anterior shoulder instability. It was hypothesized that both approaches would provide equal access to a simulated Hill-Sachs lesion. Study Design: Controlled laboratory study. Methods: Four human cadaveric shoulders were mounted in the beach-chair position. The modified posterior deltoid split approach and nonextensile deltopectoral approaches were performed. A typical Hill-Sachs lesion was simulated on the humeri. The percentage of the total surface area of the humeral head that was accessed, including access to the simulated Hill-Sachs lesion, was mapped using 3-dimensional digitizing software. Results: The deltopectoral approach provided 45% ± 15.2% access (range, 24% to 58%) to the humeral head versus 22.2% ± 6.1% (range, 17% to 30%) for the modified posterior deltoid split approach (P = .057). The modified posterior deltoid split approach enabled 100% access of the simulated Hill-Sachs lesion compared with 0% for the nonextensile deltopectoral approach. The angle of access to the articular surface was direct and perpendicular with the modified posterior deltoid split approach. Conclusion: The overall surface area of the humeral head accessed via the modified posterior deltoid split approach was less compared with the deltopectoral approach; however, the entire area of a typical Hill-Sachs lesion was able to be accessed from the modified posterior deltoid split approach, whereas this area was not well visualized from the standard deltopectoral approach. Clinical Relevance: The modified posterior deltoid split approach provided sufficient access to the humeral head for the purposes of grafting an engaging Hill-Sachs lesion in the setting of anterior shoulder instability.

First Results of NURE-Combo: A Phase II Study of Neoadjuvant Nivolumab and Nab-Paclitaxel, Followed by Postsurgical Adjuvant Nivolumab, for Muscle-Invasive Bladder Cancer.

PURPOSE: To evaluate the activity and safety of nivolumab with nab-paclitaxel as neoadjuvant therapy, followed by radical cystectomy (RC) and postsurgical adjuvant nivolumab in patients with muscle-invasive bladder cancer (MIBC). PATIENTS AND METHODS: Eligible patients had an Eastern Cooperative Oncology Group performance status of ≤1 and a T2-4aN0-1M0 stage with >50% urothelial carcinoma histology and were ineligible for or refused cisplatin-based chemotherapy. Patients received four cycles of nivolumab 360 mg once every 3 weeks + nab-paclitaxel 125 mg/m2 once on days 1 and 8, every 3 weeks, followed by RC, and then adjuvant nivolumab 360 mg once every 3 weeks × 13 cycles. The primary end point was the pathologic complete response (CR) rate (ypT0N0). Secondary end points were major pathologic response (ypT≤1N0), safety, event-free survival (EFS), and overall survival. RESULTS: Thirty-one patients were enrolled from December 2021 to June 2023; 19 (61.3%) had a cT2 stage, two (6.5%) had N1 stage, and 16 (51.6%) had a variant histology. Five patients (16.1%) received less than four full courses of neoadjuvant treatment because of treatment-related adverse events (TRAEs). Grade 3/4 TRAEs occurred in eight patients (25.8%). Twenty-eight patients underwent RC, and three refused RC after evidence of clinical CR and received a redo transurethral resection of the bladder tumor (reTURBT). The trial met its primary end point: 10 patients (32.3%; 95% CI, 16.7 to 51.4) achieved an ypT0N0 response. By including those who underwent reTURBT, 22 (70.9%; 95% CI, 55 to 87) achieved an ypT≤1N0-x response. After a median follow-up of 12 months (range, 5-22), two patients had a disease relapse after surgery. The 12-month EFS was 89.8% (95% CI, 79.5 to 100). CONCLUSION: To our knowledge, the first results from NURE-Combo trial suggest that this combination could expand the therapeutic opportunities of immune-chemotherapy in patients with MIBC.

Megakaryocyte maturation involves activation of the adaptive unfolded protein response.

Endoplasmic reticulum stress triggers the unfolded protein response (UPR) to promote cell survival or apoptosis. Transient endoplasmic reticulum stress activation has been reported to trigger megakaryocyte production, and UPR activation has been reported as a feature of megakaryocytic cancers. However, the role of UPR signaling in megakaryocyte biology is not fully understood. We studied the involvement of UPR in human megakaryocytic differentiation using PMA (phorbol 12-myristate 13-acetate)-induced maturation of megakaryoblastic cell lines and thrombopoietin-induced differentiation of human peripheral blood-derived progenitors. Our results demonstrate that an adaptive UPR is a feature of megakaryocytic differentiation and that this response is not associated with ER stress-induced apoptosis. Differentiation did not alter the response to the canonical endoplasmic reticulum stressors DTT or thapsigargin. However, thapsigargin, but not DTT, inhibited differentiation, consistent with the involvement of Ca2+ signaling in megakaryocyte differentiation.

Urachal and Nonurachal Adenocarcinomas of the Urinary Bladder: A Comprehensive Genomic Profiling Study.

PURPOSE: Although both urachal (U) and nonurachal (NU) bladder adenocarcinomas (adenoCas) share several histologic similarities, they differ in location and sometimes in therapeutic options. We analyzed the differences in genomic alterations (GAs) between these tumor entities, with the aim of identifying potential therapeutic targets for clinical trials. MATERIALS AND METHODS: Overall, 133 U and 328 NU adenoCas were analyzed. Hybrid capture-based comprehensive genomic profiling (CGP) was performed to evaluate all classes of GA. Germline status of GA was predicted using a validated somatic-germline computational method. CGP was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc). RESULTS: The most frequent GA in both U and NU cohorts included TP53 (86.5% v 81.1%) and KRAS (34.6% v 27.7%). GAs characteristic of colorectal adenoCa, such as SMAD4 (P = .069) and GNAS (P = .071), were more common in U versus NU. Conversely, TERT (P < .01) and RB1 (P = .071) were more prevalent in NU adenoCa. Notably, both U and NU adenoCas exhibited possibly targetable GA in PIK3CA (7.5% v 7.9%) and ERBB2 (6.8% v 7.6%). Biomarkers associated with potential benefit from anti-PD-1/L1 were infrequent. Median tumor mutational burden was 2.6 and 3.5 mutations per megabase for U and NU, respectively, and PD-L1 expression >1% was rare. Genomic ancestry and genomic signature distribution were similar in both tumor types. GAs were most commonly of somatic nature. Limitations include lack of clinical data, tumor heterogeneity, and retrospective nature. CONCLUSION: U and NU adenoCAs revealed differences in GA, with PIK3CA and ERBB2 being identified as putative therapeutic targets. Biomarkers of response to anti-PD-(L)1 were uncommon. Results highlight the potential of CGP to personalize treatment options of bladder adenoCa and inform clinical trial designs.

TetR-like regulator BP1026B_II1561 controls aromatic amino acid biosynthesis and intracellular pathogenesis in Burkholderia pseudomallei.

Burkholderia pseudomallei (Bp) causes the tropical disease melioidosis that afflicts an estimated 165,000 people each year. Bp is a facultative intracellular pathogen that transits through distinct intracellular stages including attachment to host cells, invasion through the endocytic pathway, escape from the endosome, replication in the cytoplasm, generation of protrusions towards neighboring cells, and host cell fusion allowing Bp infection to spread without exiting the intracellular environment. We have identified a TetR-like transcriptional regulator, BP1026B_II1561, that is up-regulated during the late stages of infection as Bp protrudes toward neighboring cells. We have characterized BP1026B_II1561 and determined that it has a role in pathogenesis. A deletional mutant of BP1026B_II1561 is attenuated in RAW264.7 macrophage and BALB/c mouse models of infection. Using RNA-seq, we found that BP1026B_II1561 controls secondary metabolite biosynthesis, fatty acid degradation, and propanoate metabolism. In addition, we identified that BP1026B_II1561 directly controls expression of an outer membrane porin and genes in the shikimate biosynthetic pathway using ChIP-seq. Transposon mutants of genes within the BP1026B_II1561 regulon show defects during intracellular replication in RAW264.7 cells confirming the role of this transcriptional regulator and the pathways it controls in pathogenesis. BP1026B_II1561 also up-regulates the majority of the enzymes in shikimate and tryptophan biosynthetic pathways, suggesting their importance for Bp physiology. To investigate this, we tested fluorinated analogs of anthranilate and tryptophan, intermediates and products of the shikimate and tryptophan biosynthetic pathways, respectively, and showed inhibition of Bp growth at nanomolar concentrations. The expression of these pathways by BP1026b_II1561 and during intracellular infection combined with the inhibition of Bp growth by fluorotryptophan/anthranilate highlights these pathways as potential targets for therapeutic intervention against melioidosis. In the present study, we have identified BP1026B_II1561 as a critical transcriptional regulator for Bp pathogenesis and partially characterized its role during host cell infection.

Developing work readiness in university graduates: a case study in mapping a university curriculum to work readiness domains in an Australian physiotherapy degree.

BACKGROUND: Recent research has identified six domains of work readiness: Practical Wisdom, Interpersonal Capabilities, Personal Attributes, Organisational Acumen, Profession Specific Knowledge and Skills, and Professionally Relevant Experiences. OBJECTIVE: Using a case study, the aim of this study was to demonstrate the process of curriculum mapping to evaluate the alignment of a university program to the work readiness framework. METHODS: A retrospective audit of curriculum material for one cohort of Macquarie University's Doctor of Physiotherapy (DPT) was undertaken. Curriculum was categorized as declared, delivered, or assessed, mapped to the six work readiness domains through qualitative content analysis, and then quantitatively scored and expressed as percentages of maximum possible scores per unit, and average units scores per semester. RESULTS: Mapping curriculum to a six domain work readiness framework revealed declared, delivered, and assessed curriculum within all six work readiness domains, with varying contributions across the degree. Mapping revealed that the Profession Specific Knowledge and Skills domain had the highest coverage of declared (M = 63%, SD = 12), delivered (M = 88%, SD = 11) and assessed (M = 80%, SD = 7) curriculum, highlighting a strength of the program. The Personal Attributes domain had the lowest coverage of declared (M = 5%, SD = 5), delivered (M = 48%, SD = 24) and assessed (M = 29%, SD = 20) curriculum, highlighting opportunities for development. CONCLUSION: Mapping curriculum to a work readiness framework allows universities to consider alignment, and the strength and opportunities for the improvement of work readiness within its curriculum.

Exploring Phylogenetic Signal in Multivariate Phenotypes by Maximizing Blomberg's K.

Due to the hierarchical structure of the tree of life, closely related species often resemble each other more than distantly related species; a pattern termed phylogenetic signal. Numerous univariate statistics have been proposed as measures of phylogenetic signal for single phenotypic traits, but the study of phylogenetic signal for multivariate data, as is common in modern biology, remains challenging. Here we introduce a new method to explore phylogenetic signal in multivariate phenotypes. Our approach decomposes the data into linear combinations with maximal (or minimal) phylogenetic signal, as measured by Blomberg's K. The loading vectors of these phylogenetic components or K-components can be biologically interpreted, and scatterplots of the scores can be used as a low-dimensional ordination of the data that maximally (or minimally) preserves phylogenetic signal. We present algebraic and statistical properties, along with two new summary statistics, KA and KG, of phylogenetic signal in multivariate data. Simulation studies showed that KA and KG have higher statistical power than the previously suggested statistic Kmult, especially if phylogenetic signal is low or concentrated in a few trait dimensions. In two empirical applications to vertebrate cranial shape (crocodyliforms and papionins), we found statistically significant phylogenetic signal concentrated in a few trait dimensions. The finding that phylogenetic signal can be highly variable across the dimensions of multivariate phenotypes has important implications for current maximum likelihood approaches to phylogenetic signal in multivariate data.