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In the companion Perspective 'Past and future of human developmental biology' (Hopwood, 2024), historian Nick Hopwood proposes that the field of human developmental biology has gone through periods of attention and neglect. Development invited researchers from the field to respond to this idea. In this article, published to coincide with the 10th anniversary of Development's 'From Stem Cells to Human Development' meeting, researchers from eight countries comment on how they believe their local legal, political, regulatory, societal and technological frameworks are influencing the field's trajectory.

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OBJECTIVE: We evaluated survival outcomes by primary tumor site in synovial sarcoma (SS) patients with localized and metastatic disease at diagnosis. METHODS: We conducted a retrospective review of 504 SS patients diagnosed from 1974 to 2020. Kaplan-Meier method, log-rank test, and Cox-proportional hazards regression were used. RESULTS: Among 504 patients, 401 (79.6%) presented with localized disease, and 103 (20.4%) with metastases. For patients with localized disease, (1) 5-year OS by tumor site was as follows: 80% (95% CI, 67%-89%) for head/neck, 30% (95% CI, 18%-42%) for intrathoracic, 51% (95% CI, 35%-65%) for abdomen/pelvis, 71% (95% CI, 62%-79%) for proximal-extremity, and 83% (71%, 91%) for distal-extremity. (2) On multivariable analysis, tumor site (compared with proximal-extremity: intrathoracic tumors [HR: 1.95; 95% CI, 1.22-3.16]; hand/foot [HR: 0.52; 95% CI, 0.28-0.97]), tumor size (compared with <5 cm, 5-10 cm [HR: 1.80; 95% CI, 1.14-2.85]; ≥10 cm [HR: 4.37; 95% CI, 2.69-7.11]), and use of neo/adjuvant radiation (HR: 0.54; 95% CI, 0.37-0.79) remained significantly associated with OS. For patients with metastatic disease, (1) 5-year OS was 12% (95% CI, 6%-21%) and (2) the only factor that remained significantly associated with OS on multivariable analysis was surgical resection for the primary tumor (HR: 0.14; 95% CI, 0.08-0.26). CONCLUSIONS: The primary tumor location plays a significant role in predicting outcomes for patients with localized SS. Even though patients present with metastatic disease, surgical resection of the primary tumor improves their survival. These findings are critical for patient counseling and designing a personalized treatment plan that reflects the corresponding outcomes.

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BACKGROUND: Pancreatoduodenectomy (PD) for pancreatic cancer has a profound impact on patients' lives. However, the long-term financial implications are poorly understood. OBJECTIVE: Assess the financial burden of long-term survivors who underwent PD. METHODS: Patients who underwent PD between January 2011 and June 2019 were identified. To evaluate the long-term financial burden, patients surviving ≥ 3 years post-resection were prospectively surveyed using the Comprehensive Score for financial Toxicity (COST-FACIT) and a customized institutionally developed questionnaire. A logistic regression model predicting high financial toxicity was used to identify predictive factors. RESULTS: Among 238 eligible patients, 137 (57.6%) responded. Responders had a median age of 66 (59-73) years, with 86.7% identifying as financial prosperous or comfortable. However, 33.3% experienced financial distress due to treatment costs, 27.3% demonstrated high financial toxicity on the COST-FACIT survey, and 37.2% made sacrifices to afford treatment. Only 8.9% stated that the treatment costs influenced their decisions, and the majority (85.9%) did not discuss financial implications with healthcare providers. Multivariable analysis identified younger age as a risk factor for high financial toxicity. CONCLUSION: One in three long-term survivors experienced high financial toxicity, with younger age being a predictor. This emphasizes the need for efforts to provide comprehensive support and guidance to patients to navigate their oncological journey.

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Frequently, problems can be solved in more than one way. In modern computerized environments, more ways than ever exist. Naturally, human problem solvers do not always decide for the best-performing strategy available. One underlying reason might be the inability to continuously and correctly monitor each strategy's performance. Here, we supported some of our participants' monitoring ability by providing written feedback regarding their speed and accuracy. Specifically, participants engaged in an object comparison task, which they were asked to solve with one of two strategies: an internal strategy (mental rotation) or an extended strategy (manual rotation). After receiving no feedback (30 participants), trialwise feedback (30 participants), or blockwise feedback (30 participants) in these no choice trials, all participants were asked to estimate their performance with both strategies and were then allowed to freely choose between strategies in choice trials. Results indicated that written feedback improves explicit performance estimates. However, results also indicated that such increased awareness does not guarantee improved strategy choice and that attending to written feedback might tamper with more adaptive ways inform the choice. Thus, we advise against prematurely implementing written feedback. While it might support adaptive strategy choice in certain environments, it did not in the present setup. We encourage further research that improves the understanding of how we monitor the performance of different cognitive strategies. Such understanding will help create interventions that support human problem solvers in making better choices in the future.

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A quantum emitter interacting with photons in a single optical-mode constitutes a one-dimensional atom. A coherent and efficiently coupled one-dimensional atom provides a large nonlinearity, enabling photonic quantum gates. Achieving a high coupling efficiency (ß factor) and low dephasing is challenging. Here, we use a semiconductor quantum dot in an open microcavity as an implementation of a one-dimensional atom. With a weak laser input, we achieve an extinction of 99.2% in transmission and a concomitant bunching in the photon statistics of g^{(2)}(0)=587, showcasing the reflection of the single-photon component and the transmission of the multi-photon components of the coherent input. The tunable nature of the microcavity allows ß to be adjusted and gives control over the photon statistics-from strong bunching to antibunching-and the phase of the transmitted photons. We obtain excellent agreement between experiment and theory by going beyond the single-mode Jaynes-Cummings model. Our results pave the way towards the creation of exotic photonic states and two-photon phase gates.

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BACKGROUND: An innovative, integrative care model for people with Parkinson (PRIME Parkinson) has gradually been implemented in a selected region of the Netherlands since 2021. A prospective evaluation of this model (PRIME-NL study) was initiated in parallel, spanning the year prior to implementation (baseline) and the implementation period. Following publication of the original study protocol, the COVID-19 crisis delayed implementation of the full PRIME Parkinson care model by two years and hampered the recruitment of study participants. OBJECTIVE: To describe which methodological adjustments were made to the study protocol because of these developments. METHODS: We compare various outcomes between a region where PRIME Parkinson care was implemented (innovation region) versus the rest of the Netherlands (usual care region). We use healthcare claims data of virtually all people with Parkinson in the Netherlands and annual questionnaires in a representative subsample of 984 people with Parkinson, 566 caregivers and 192 healthcare professionals. Four major methodological adjustments had to be made since publication of the original protocol. First, we extended the evaluation period by two years. Second, we incorporated annual process measures of the stage of implementation of the new care model. Third, we introduced a real-time iterative feedback loop of interim results to relevant stakeholders. Fourth, we updated the statistical analysis plan. DISCUSSION: This manuscript provides transparency in how the design and analyses of the evaluation study had to be adapted to control for external influences in a dynamic environment, including eruption of the COVID-19 crisis. Our solutions could serve as a template for evaluating other complex healthcare interventions in a dynamic environment.

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Introduction The internet is increasingly the first port of call for patients introduced to new treatments. Unfortunately, many websites are of poor quality, thereby limiting patients' ability to make informed health decisions. Within thoracic surgery, the treatment options for pneumothoraces may be less intuitive for patients to understand compared to procedures such as lobectomies and wedge resections. Therefore, patients must receive high-quality information to make informed treatment decisions. No study to date has evaluated online information regarding pneumothorax surgery. Knowledge regarding the same may allow physicians to recommend appropriate websites to patients and supplement remaining knowledge gaps. Objective This study aims to evaluate the content, readability, and reliability of online information regarding pneumothorax surgery. Methods A total of 11 search terms including "pneumothorax surgery," "pleurectomy," and "pleurodesis" were each entered into Google, Bing, and Yahoo. The top 20 websites found through each search were screened, yielding 660 websites. Only free websites designed for patient consumption that provided information on pneumothorax surgery were included. This criterion excluded 581 websites, leaving 79 websites to be evaluated. To evaluate website reliability, the Journal of American Medical Association (JAMA) and DISCERN benchmark criteria were applied. To evaluate the readability, 10 standardized tools were utilized including the Flesch-Kincaid Reading Ease Score. To evaluate website content, a novel, self-designed 10-part questionnaire was utilized to assess whether information deemed essential by the authors was included. It evaluated whether websites comprehensively described the surgery process for patients, including pre- and post-operative care. Website authorship and year of publication were also noted. Results The mean JAMA score was 1.69 ± 1.29 out of 4, with only nine websites achieving all four reliability criteria. The median readability score was 13.42 (IQR: 11.48-16.23), which corresponded to a 13th-14th school grade standard. Only four websites were written at a sixth-grade reading level. In the novel content questionnaire, 31.6% of websites (n = 25) did not mention any side effects of pneumothorax surgery. Similarly, 39.2% (n = 31) did not mention alternative treatment options. There was no correlation between the date of website update and JAMA (r = 0.158, p = 0.123), DISCERN (r = 0.098, p = 0.341), or readability (r = 0.053, p = 0.606) scores. Conclusion Most websites were written above the sixth-grade reading level, as recommended by the US Department of Health and Human Services. Furthermore, the exclusion of essential information regarding pneumothorax surgery from websites highlights the current gaps in online information. These findings emphasize the need to create and disseminate comprehensive, reliable websites on pneumothorax surgery that enable patients to make informed health decisions.

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BACKGROUND: Moderately hypofractionated, preoperative radiotherapy in patients with soft tissue sarcomas (HYPORT-STS; ClinicalTrials.gov identifier NCT03819985) investigated a radiobiologically equivalent, moderately hypofractionated course of preoperative radiotherapy (RT) 15 × 2.85 Gy in patients with soft tissue sarcoma (STS). Here, the authors report longer term follow-up to update local control and report late toxicities, as well as functional and patient-reported outcomes. METHODS: HYPORT-STS was a single-center, open-label, single-arm, prospective phase 2 clinical trial that enrolled 120 eligible adult patients with localized STS of the extremities or superficial trunk between 2018 and 2021. Patients received a 3-week course of preoperative RT followed by surgery 4-8 weeks later. End points and follow-up were analyzed from the date of surgery. RESULTS: The median follow-up was 43 months (interquartile range, 37-52 months), and the 4-year local recurrence-free survival rate was 93%. Overall RT-related late toxicities improved with time from local therapy (p < .001), and few patients had grade ≥2 toxicities (9%; n = 8 of 88) at 2 years. These included: 2% grade ≥2 skin toxicity, 2% fibrosis, 3% lymphedema, and 1% joint stiffness. Four patients (3%) had bone fractures. Both functional outcomes, as measured by the Musculoskeletal Tumor Society Rating Scale (p < .001), and quality of life, as measured by the Functional Assessment of Cancer Therapy-General (p < .001), improved with time from treatment, and both measures were better in follow-up at 2 years compared with baseline. CONCLUSIONS: Long-term follow up suggests that moderately hypofractionated preoperative RT for patients with STS is safe and effective. Higher grade late toxicities affect a minority of patients. Late toxicities decrease over time, whereas functional outcomes and health-related quality of life seem to improve with more time from combined modality treatment.

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Salvia hispanica L. (Chia), a member of the Lamiaceae, is an economically important crop in Mesoamerica, with health benefits associated with its seed fatty acid composition. Chia varieties are distinguished based on seed color including mixed white and black (Chia pinta) and black (Chia negra). To facilitate research on Chia and expand on comparative analyses within the Lamiaceae, we generated a chromosome-scale assembly of a Chia pinta accession and performed comparative genome analyses with a previously published Chia negra genome assembly. The Chia pinta and Chia negra genome sequences were highly similar as shown by a limited number of single nucleotide polymorphisms and extensive shared orthologous gene membership. However, there is an enrichment of terpene synthases in the Chia pinta genome relative to the Chia negra genome. We sequenced and analyzed the genomes of 20 Chia accessions with differing seed color and geographic origin revealing population structure within S. hispanica and interspecific introgressions of Salvia species. As the genus Salvia is polyphyletic, its evolutionary history remains unclear. Using large-scale synteny analysis within the Lamiaceae and orthologous group membership, we resolved the phylogeny of Salvia species. This study and its collective resources further our understanding of genomic diversity in this food crop and the extent of interspecies hybridizations in Salvia.

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BACKGROUND: Synovial sarcoma (SS) is a rare soft-tissue cancer. Existing literature encompasses Surveillance, Epidemiology, and End Results (SEER) data-based research on SS explaining the incidence-prevalence in general, by subtypes, and by age at diagnosis. Therefore, this study aimed to fill in the gap of knowledge about measures of disease occurrence and burden of SS by tumor site using the SEER database. METHODS: In this cross-sectional study, primary SS patients were selected from SEER 17 Registries, Nov. 2021 (2000-2020) using ICD-O-3 codes 9040, 9041, 9042, and 9043. Patients with additional cancers were excluded. The primary tumor site was categorized into (1) head/neck, (2) internal thorax, (3) abdomen/pelvis, (4) upper extremity, and (5) lower extremity using ICD-10CM codes. Five outcomes were analyzed: age-adjusted incidence rate, 5-year limited-duration prevalence rate, incidence-based mortality, case-fatality rate, and overall survival. RESULTS: From 2000-2020, the overall age-adjusted incidence rate was 0.15 per 100,000; the 5-year limited duration prevalence rate was 0.56 per 100,000; and the incidence-based mortality rate was 0.06 per 100,000 people. The case-fatality and 5-year OS rates were 39.2 % and 62.9 %, respectively. Lower extremity had the highest incidence of 0.07 (estimated 1166 cases), prevalence of 0.36 (estimated 224 cases), and mortality rate of 0.025 (estimated 429 deaths) per 100,000. The other four locations had much closer rates with each other. Intrathoracic SS had the highest case-fatality rate of 71.5 % (148/207) and lowest 5-year OS of 26.0 % (95 % CI: 19.6 %, 32.9 %) than other sites. CONCLUSION: Based on the measures of disease frequency, the most common primary tumor site is the lower extremity, followed by the upper extremity, abdomen/pelvis, internal thorax, and head/neck. The least favorable primary location is the internal thorax. Those with a primary location of the upper extremity have the longest overall survival, followed by the head/neck, lower extremity, abdomen/pelvis, and internal thorax.

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Background: The past few years have seen a 50% increase in breast implant explantations. Patients with ptotic breasts may desire mastopexy, although conventional techniques are often invasive. We describe our experience with the omega mastopexy technique after breast implant explantation and capsulectomy. Methods: In the past 2 years, 10 patients with breast Regnault classification ptosis grade I-III underwent the omega mastopexy technique following breast implant explantation and capsulectomy. A detailed description of our operating technique is provided. Results: This series includes a total of 10 patients. The median age was 48.5 (IQR 42.8-52.5), median body mass index 26 (23.8-28.3) and median implant volume 355 (IQR 325-375). Excellent and stable aesthetic results were achieved without recurring ptosis. One patient, an active smoker, underwent reexcision after 1 year due to hypertrophic scars. No complications have been reported until this date at 2 years follow-up. Conclusions: The omega mastopexy technique offers an excellent alternative to classic lifting techniques for ptotic breasts after breast implant explantation. Patients with increased risk of wound healing impairment are especially likely to benefit.

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BACKGROUND: Two-stage revision for periprosthetic joint infection (PJI) in patients who have undergone segmental replacement of the distal femur or proximal tibia after tumor resection can be associated with considerable morbidity, pain, and risk of complications because the procedure often results in removal of long, well-fixed stems from the diaphysis. A less-aggressive surgical approach, such as debridement, antibiotics, and implant retention (DAIR), may be attractive to patients and surgeons because of less morbidity, but the likelihood of eradicating infection in comparison to the traditional two-stage revision is not well established for oncology patients. Furthermore, the relative risk of subsequent amputation for DAIR versus two-stage revision has not been defined for this population. QUESTIONS/PURPOSES: (1) How does DAIR compare with two-stage revision in terms of infection control for patients with distal femoral or proximal tibial segmental modular endoprostheses? (2) Is DAIR as an initial procedure associated with an increased risk of amputation compared with two-stage revision for infection? METHODS: From the longitudinally maintained orthopaedic oncology surgical database at our institution, we identified 69 patients who had been treated for a clinical diagnosis of PJI at the knee between 1993 and 2015. We excluded 32% (22) of patients who did not meet at least one of the major criteria of the Musculoskeletal Infection Society (MSIS) for PJI, 3% (2) of patients who underwent immediate amputation, 3% (2) of patients who had a follow-up time of < 24 months, and 7% (5) of patients who did not have a primary tumor of the distal femur or proximal tibia. The study consisted of 38 patients, of whom eight underwent two-stage revision, 26 underwent DAIR, and four underwent extended DAIR (removal of all segmental components but with retention of stems and components fixed in bone) for their initial surgical procedure. To be considered free of infection, patients had to meet MSIS standards, including no positive cultures, drainage, or surgical debridement for a minimum of 2 years from the last operation. Factors associated with time-dependent risk of infection relapse, clearance, amputation, and patient survival were analyzed using Kaplan-Meier survivorship curves and the log-rank test to compare factors. Association of demographic and treatment factors was assessed using chi-square and Fisher exact tests. RESULTS: Continuous infection-free survival at 5 years was 16% (95% CI 2% to 29%) for patients undergoing DAIR compared with 75% (95% CI 45% to 100%) for patients undergoing two-stage revision (p = 0.006). The median (range) number of total surgical procedures was 3 per patient (1 to 10) for DAIR and 2 (2 to 5) for two-stage revision. Twenty-nine percent (11 of 38) of patients eventually underwent amputation. Survival without amputation was 69% (95% CI 51% to 86%) for DAIR compared with 88% (95% CI 65% to 100%) for two-stage revision at 5 years (p = 0.34). The cumulative proportion of patients achieving infection-free status (> 2 years continuously after last treatment) and limb preservation was 58% (95% CI 36% to 80%) for patients initially treated with DAIR versus 87% (95% CI 65% to 100%) for patients first treated with two-stage revision (p = 0.001). CONCLUSION: Infection control was better with two-stage revision than DAIR. The chance of eventual clearance of infection with limb preservation was better when two-stage revision was chosen as the initial treatment. However, the loss to follow-up in the two-stage revision group would likely make the true proportion of infection control lower than our estimate. Our experience would suggest that the process of infection eradication is a complex and difficult one. Most patients undergo multiple operations. Nearly one-third of patients eventually underwent amputation, and this was a serious risk for both groups. While we cannot strongly recommend one approach over the other based on our data, we would still consider the use of DAIR in patients who present with acute short duration of symptoms (< 3 weeks), no radiographic signs of erosion around fixed implants, and organisms other than Staphylococcus aureus. We would advocate the extended DAIR procedure with removal of all segmental or modular components, and we would caution patients that there is a high likelihood of needing further surgery. A prospective trial with strict adherence to indications may be needed to evaluate the relative merits of an extended DAIR procedure versus a two-stage revision. LEVEL OF EVIDENCE: Level III, therapeutic study.

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Drought stress substantially impacts crop physiology resulting in alteration of growth and productivity. Understanding the genetic and molecular crosstalk between stress responses and agronomically important traits such as fibre yield is particularly complicated in the allopolyploid species, upland cotton (Gossypium hirsutum), due to reduced sequence variability between A and D subgenomes. To better understand how drought stress impacts yield, the transcriptomes of 22 genetically and phenotypically diverse upland cotton accessions grown under well-watered and water-limited conditions in the Arizona low desert were sequenced. Gene co-expression analyses were performed, uncovering a group of stress response genes, in particular transcription factors GhDREB2A-A and GhHSFA6B-D, associated with improved yield under water-limited conditions in an ABA-independent manner. DNA affinity purification sequencing (DAP-seq), as well as public cistrome data from Arabidopsis, were used to identify targets of these two TFs. Among these targets were two lint yield-associated genes previously identified through genome-wide association studies (GWAS)-based approaches, GhABP-D and GhIPS1-A. Biochemical and phylogenetic approaches were used to determine that GhIPS1-A is positively regulated by GhHSFA6B-D, and that this regulatory mechanism is specific to Gossypium spp. containing the A (old world) genome. Finally, an SNP was identified within the GhHSFA6B-D binding site in GhIPS1-A that is positively associated with yield under water-limiting conditions. These data lay out a regulatory connection between abiotic stress and fibre yield in cotton that appears conserved in other systems such as Arabidopsis.

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RATIONALE: Healthcare systems remain disease oriented despite growing sustainability concerns caused by inadequate management of patients with multimorbidity. Comprehensive care programmes (CCPs) can play an important role in streamlining care delivery, but large differences in setup and results hinder firm conclusions on their effectiveness. Many elements for successful implementation of CCPs are identified, but strategies to overcome barriers and embed programmes within health systems remain unknown. AIMS AND OBJECTIVES: To address this knowledge gap through a detailed study of implementing a CCP in a Dutch hospital setting, including patient experiences, facilitators, barriers and ways to overcome those barriers. Additionally, this study aims to explore effects on patient satisfaction and healthcare use. METHODS: A qualitative study design with 39 semistructured interviews and focus groups between July 2020 and February 2023 with 16 patients and 17 involved professionals. Additionally, effects on quantitative outcomes for patient satisfaction (PACIC-20) and healthcare use were explored. RESULTS: Professionals expressed a wide range of topics related to implementation and ways to overcome barriers at hospital and system level. Alterations in the design to accommodate varying care demands, focus on inclusions through referrals, and lack of long-term support and appropriate financing were key topics. Patients expressed varying experiences, stated a strong desire for comprehensive information, and emphasised the importance of trust in caregivers. Patient satisfaction showed no effects, while healthcare use showed slight decreases in trends, but patient numbers were limited. CONCLUSION: The introduction of a CCP is feasible, and exploratory analysis on effectiveness shows lower hospital care use without decreasing patient satisfaction. However, this is accompanied by several challenges that show current fragmented systems still do not support implementation of integrated care initiatives. Overcoming those comes with substantial costs and may require a strong bottom-up implementation within a motivated team and actions on all levels of healthcare systems.

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PURPOSE: For patients with vestibular schwannomas (VS), a conservative observational approach is increasingly used. Therefore, the need for accurate and reliable volumetric tumor monitoring is important. Currently, a volumetric cutoff of 20% increase in tumor volume is widely used to define tumor growth in VS. The study investigates the tumor volume dependency on the limits of agreement (LoA) for volumetric measurements of VS by means of an inter-observer study. METHODS: This retrospective study included 100 VS patients who underwent contrast-enhanced T1-weighted MRI. Five observers volumetrically annotated the images. Observer agreement and reliability was measured using the LoA, estimated using the limits of agreement with the mean (LOAM) method, and the intraclass correlation coefficient (ICC). RESULTS: The 100 patients had a median average tumor volume of 903 mm3 (IQR: 193-3101). Patients were divided into four volumetric size categories based on tumor volume quartile. The smallest tumor volume quartile showed a LOAM relative to the mean of 26.8% (95% CI: 23.7-33.6), whereas for the largest tumor volume quartile this figure was found to be 7.3% (95% CI: 6.5-9.7) and when excluding peritumoral cysts: 4.8% (95% CI: 4.2-6.2). CONCLUSION: Agreement limits within volumetric annotation of VS are affected by tumor volume, since the LoA improves with increasing tumor volume. As a result, for tumors larger than 200 mm3, growth can reliably be detected at an earlier stage, compared to the currently widely used cutoff of 20%. However, for very small tumors, growth should be assessed with higher agreement limits than previously thought.

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Magnetic field hyperthermia relies on the intra-tumoural delivery of magnetic nanoparticles by interstitial injection, followed by their heating on exposure to a remotely-applied alternating magnetic field (AMF). This offers a potential sole or adjuvant route to treating drug-resistant tumours for which no alternatives are currently available. However, two challenges in nanoparticle delivery currently hinder the effective clinical translation of this technology: obtaining enough magnetic material within the tumour to enable sufficient heating; and doing this accurately to limit or avoid damage to surrounding healthy tissue. A further complication is the lack of established methods to non-invasively quantify nanoparticle biodistribution, which is necessary to evaluate the performance of improved delivery strategies. Here we employ 111In radiolabelling and single-photon emission computed tomography (SPECT) to non-invasively quantify distribution of a clinical grade iron-oxide-based nanoparticle in a mouse model of melanoma. We show that compared to manual injection, ultrasound guided delivery together with syringe-pump-controlled infusion improves both the nanoparticle concentration within the tumour, and the accuracy of delivery - reducing off-target peri-tumoural delivery. Following AMF heating, injected melanomas shrank significantly compared to non-injected controls, validating therapeutic efficacy. Systemic off-target delivery was quantified and extrapolated to predict off-target energy absorbance within safe limits for the main sites of background accumulation. With many nanoparticle-based therapies currently in development for cancer, this image-guided delivery strategy has wide potential impact beyond the field of magnetic hyperthermia. Future use in representative patient cohorts would also be enabled by the high clinical availability of both SPECT and ultrasound imaging.

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(1) Background: Local therapies offer a potentially curative approach for patients with oligometastatic colorectal cancer (CRC). An evidence-based consensus recommendation for systemic therapy following definitive locoregional therapy is lacking. Tumor-informed circulating tumor DNA (ctDNA) might provide information to help guide management in this setting. (2) Methods: A multi-institutional retrospective study was conducted, including patients with CRC that underwent curative-intent locoregional therapy to an isolated site of metastatic disease, followed by tumor-informed ctDNA assessment. The Kaplan-Meier method and log-rank tests were used to compare disease-free survival based on ctDNA results. ctDNA test performance was compared to carcinoembryonic antigen (CEA) test results using McNemar's test. (3) Results: Our study cohort consisted of 87 patients treated with locoregional interventions who underwent ctDNA testing. The initial ctDNA test post-intervention was positive in 28 patients and negative in 59 patients. The median follow-up time was 14.0 months. Detectable ctDNA post-intervention was significantly associated with early disease recurrence, with a median disease-free survival (DFS) of 6.63 months compared to 21.30 months in ctDNA-negative patients (p < 0.001). ctDNA detected a numerically higher proportion of recurrences than CEA (p < 0.097). Post-intervention systemic therapy was not associated with improved DFS (p = 0.745). (4) Conclusions: ctDNA results are prognostically important in oligometastatic CRC, and further prospective studies are urgently needed to define its role in guiding clinical decisions.

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Introduction: This study aimed to assess the effect of integrated palliative care (IPC) on potentially inappropriate end- of-life care and healthcare-costs in the last 30 days of life in the Netherlands. Methods: Nationwide health-insurance claims data were used to assess potentially inappropriate end-of-life care (≥2 emergency room visits; ≥2 hospital admissions; >14 days hospitalization; chemotherapy; ICU admission; hospital death) and healthcare-costs in all deceased adults in IPC regions pre- and post- implementation and in those receiving IPC compared to a 1:2 matched control group. Results: In regions providing IPC deceased adults (n = 37,468) received significantly less potentially inappropriate end-of-life care post-implementation compared to pre-implementation (26.5% vs 27.9%; p < 0.05). Deceased adults who received IPC (n = 210) also received significantly less potentially inappropriate end-of-life care compared to a matched control group (14.8% vs 28.3%; p < 0.05). Mean hospital costs significantly decreased for deceased adults who received IPC (€2,817), while mean costs increased for general practitioner services (€311) and home care (€1,632). Discussion: These results highlight the importance of implementation of integrated palliative care and suitable payment. Further research in a larger sample is needed. Conclusion: This study shows less potentially inappropriate end-of-life care and a shift in healthcare costs from hospital to general practitioner and home care with IPC.

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Recently developed small-molecule inhibitors of the lysosomal protease dipeptidyl peptidase 1 (DPP1), also known as cathepsin C (CatC), can suppress suppurative inflammation in vivo by blocking the processing of zymogenic (pro-) forms of neutrophil serine proteases (NSPs), including neutrophil elastase, proteinase 3, and cathepsin G. DPP1 also plays an important role in activating granzyme serine proteases that are expressed by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. Therefore, it is critical to determine whether DPP1 inhibition can also cause off-target suppression of CTL/NK-cell-mediated killing of virus-infected or malignant cells. Herein, we demonstrate that the processing of human granzymes A and B, transitioning from zymogen to active proteases, is not solely dependent on DPP1. Thus, the killing of target cells by primary human CD8+ T cells, NK cells, and gene-engineered anti-CD19 CAR T cells was not blocked in vitro even after prior exposure to high concentrations of the reversible DPP1 inhibitor brensocatib. Consistent with this observation, the turnover of model granzyme A/B peptide substrates in the human CTL/NK cell lysates was not significantly reduced by brensocatib. In contrast, preincubation with brensocatib almost entirely abolished (>90%) both the cytotoxic activity of mouse CD8+ T cells and granzyme substrate turnover. Overall, our finding that the effects of DPP1 inhibition on human cytotoxic lymphocytes are attenuated in comparison to those of mice indicates that granzyme processing/activation pathways differ between mice and humans. Moreover, the in vitro data suggest that human subjects treated with reversible DPP1 inhibitors, such as brensocatib, are unlikely to experience any appreciable deficits in CTL/NK-cell-mediated immunities.

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Two-directional beam-tracking (2DBT) is a method for phase-contrast imaging and tomography that uses an intensity modulator to structure the X-ray beam into an array of independent circular beamlets that are resolved by a high-resolution detector. It features isotropic spatial resolution, provides two-dimensional phase sensitivity, and enables the three-dimensional reconstructions of the refractive index decrement, δ, and the attenuation coefficient, µ. In this work, the angular sensitivity and the spatial resolution of 2DBT images in a synchrotron-based implementation is reported. In its best configuration, angular sensitivities of ∼20 nrad and spatial resolution of at least 6.25 µm in phase-contrast images were obtained. Exemplar application to the three-dimensional imaging of soft tissue samples, including a mouse liver and a decellularized porcine dermis, is also demonstrated.

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