bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II clinical evaluation of radiofrequency ablation (RFA) combined with regorafenib and toripalimab in patients with colorectal cancer with liver metastases.
Authors: Wang Zhiqiang , Ouyang Hui , Luo Huiyan , Gao Fei , Mie Man , Ren Chao , Li Ji-Bin , Fu Haiyan , Huang Jin Shan
Published: June 2024

3566

Background: In several clinical studies, the combination of anti-programmed cell death protein 1 (anti-PD-1) antibodies with targeted antiangiogenic agents has demonstrated clinical benefits for patients with metastatic colorectal cancer (mCRC). However, individuals with liver metastases have shown suboptimal responses. Prior preclinical study indicates a synergistic efficacy of radiofrequency ablation (RFA) when employed in conjunction with immunotherapy. The study aimed to explore whether RFA combined with regorafenib and toripalimab (an anti-PD-1 antibody) could provide better outcomes in patients with colorectal cancer liver metastases. Methods: Using Simon's two-stage design, a total of 32 subjects were required for enrollment, with10 subjects included in stage 1. If there were no or less patients having response, the study would be terminated; otherwise, it would proceed to stage 2, enrolling an additional 22 subjects. The cohort consisted of 10 microsatellite stable (MSS) mCRC patients with multiple liver metastases who had previously failed fluorouracil, oxaliplatin, irinotecan, with or without targeted therapy. RFA was performed on a single hepatic lesion, with others designated as target lesions. Treatment with regorafenib and toripalimab commenced one week post-RFA, following a 4-week cycle. Toripalimab was administered intravenously biweekly, and regorafenib was given orally at daily dose of 80 mg (three weeks on, one week off, in a 4-week period). The primary endpoint was response rate. Results: Ten patients (3 women) were enrolled in this study, with ages ranging from 26 to 76 years (median: 52 years), and 60% being 52 years or older.Seventy percent had ECOG performance status (PS) of 0; 60% had primary colon tumors; 90% presented with synchronous liver metastases, and 80% had both intrahepatic and extrahepatic metastases. Half of the participants achieved stable disease; however, none exhibited confirmed partial or complete responses. The median progression-free survival was 3.3 months, and the median overall survival reached 11.3 months. The median number of cycles was two (range: 0.5 to 3), with 60% undergoing at least two cycles. Adverse events (AEs) included hand-foot syndrome, liver dysfunction, fatigue, abdominal distension, and thrombocytopenia. The most frequently reported AE was hand-foot syndrome, occurring in 50% of patients. Serious AEs (grade≥3) potentially related to treatment included hand-foot syndrome and hyperbilirubinemia, each with an incidence of 10%. Notably, one patient experienced hyperprogression during immunotherapy. Conclusions: The combination of RFA, regorafenib, and toripalimab has not shown encouraging efficacy in patients with CRC liver metastases. However, the observed safety profile is acceptable. Clinical trial information: NCT05485909 .
A phase II, multicenter, open-label study of polyPEPI1018 in combination with atezolizumab in participants with relapsed or refractory microsatellite-stable metastatic colorectal (MSS mCRC) cancer (Oberto-301).
Authors: Hubbard Joleen M. , Ahn Daniel H. , Jones Jeremy Clifton , Zhu Mojun , Wittenberger Kathleen , Csiszovszki Zsolt , Somogyi Eszter , Lorincz Orsolya , Molnar Levente , Tóth József , Youssoufian Hagop , Toke Eniko Rita
Published: June 2024

3594

Background: The efficacy of checkpoint inhibitor immunotherapy in MSI-H mCRC has not been replicated in MSS mCRC. Therefore, additional interventions are needed to convert immunologically “cold” MSS CRC to “hot” tumors resembling MSI-H tumors. PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine containing 12 immunogenic epitopes derived from 7 shared tumor antigens which demonstrated early evidence of clinical activity in first-line MSS mCRC. Methods: Patients with MSS mCRC who have progressed on 2-3 lines of prior chemotherapy regimen received PolyPEPI1018 (1.2 mg, sc) and atezolizumab (1,200 mg, iv) Q3W until disease progression or unacceptable toxicity. The primary endpoint was safety. A Simon 2-stage design was applied. Data on objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and correlation studies will be presented. Results: 18 patients (66 % female) were enrolled for stage 1 of the study. Median age was 54 years (range 38–79), 50% had liver metastases and 67% received at least 3 lines of prior therapies. PD-L1 expression was <1% for 85% of patients. The combination was well-tolerated; most common side effect related to treatment was Grade (Gr) 1-2 local skin reaction (n=22). Gr 2 events (n=2) at least possibly related to treatment were nausea, pyrexia and increased blood alkaline phosphatase. There were no Gr 3-5 events or study discontinuation due to treatment AE. The ORR was 0% and the DCR was 61%. The mPFS was 2.7 months (95%CI 1.4-4.0) and the mOS was not reached (95%CI 8.75 – NE months) at the data cut-off date. Ex-vivo FluoroSpot identified 13/16 subjects with robust, vaccine-specific CD8+ and/or CD4+ T cell responses detected against multiple vaccine antigens. For patients with available biopsy pairs (n=8), both the average PD-L1 expression (IC%, p=0.029) and the density of CD8+ tumor-infiltrating lymphocytes (TILs, p=0.019) were significantly increased, post-treatment. Patients with increased PFS (> 12 weeks) had both higher levels of post-treatment PD-L1 (p=0.007) and TILs (p=0.016) than patients with PFS ≤ 12 weeks. Conclusions: PolyPEPI1018 in combination with atezolizumab was well-tolerated with no Grade 3 AEs observed. Despite no objective tumor responses could be detected, correlative data suggest contribution of PolyPEPI1018-induced immune responses to the modulation of tumor microenvironment and to improved disease control. The study did not proceed to stage 2; it is on-going for the collection of survival data. Clinical trial information: NCT05243862 .
Preoperative (neoadjuvant) therapy with tislelizumab for locally advanced colorectal cancer with high microsatellite instability or deficient mismatch repair: An open-label, single-arm, multicenter phase II study.
Authors: Ding Ke-Feng , Chen Gong , Ye Yao , Liu Yue , Sun Yanlai , Gao Yang , Zhang Jingdong , Wei Shaozhong , Li Cong , Li Dandan , Zhou Yanbing , Liu Mulin , Zhang Juan , Zhang Lilin , Kong Dalu
Published: June 2024

3599

Background: Tislelizumab (TIS), an anti-programmed cell death protein 1 (PD-1) antibody, demonstrated improved anti-tumor response and tolerable safety in patients (pts) with previously treated, locally advanced unresectable or metastatic microsatellite instability high/deficient mismatch repair (MSI-H/dMMR) solid tumors, including colorectal cancer (CRC; NCT03736889). Recent studies of other anti-PD-1 antibodies indicate potential clinical benefit of neoadjuvant anti-PD-1 therapy in pts with resectable MSI-H/dMMR CRC. Here, we report efficacy and safety outcomes of neoadjuvant TIS from a multicenter phase II trial (NCT05116085) in this population. Methods: Pts aged ≥18 years with stage II/III MSI-H/dMMR CRC, ECOG PS 0-1, evaluable disease per RECIST v1.1, and eligible for R0 (complete) resection were enrolled. Pts received TIS 200 mg IV every 3 weeks for 3 cycles followed by surgical resection within 10 weeks of first TIS dose. The primary endpoint was major pathological response (MPR) rate (proportion of pts with ≤10% residual viable tumor in the surgically resected primary tumor). Secondary endpoints included pathological complete response (pCR) rate (proportion of pts with absence of residual tumor in the surgically resected specimen), and safety. The R0 resection rate was an exploratory endpoint. Results: Overall, 33 pts were enrolled across eight sites in China. The median age of enrolled pts was 52.0 years (range: 23-84), 14 (42.4%) pts were male. Ten (30.3%) pts had rectal cancer and 23 (69.7%) colon cancer. At study entry, clinical tumor (T) stage was reported as T2, T3, and T4 in 1 (3.0%), 7 (21.2%), and 25 (75.8%) pts, respectively, and node (N) stage as N0, N1, and N2 in 6 (18.2%), 14 (42.4%), and 13 (39.4%) pts, respectively. All pts had a metastasis (M) stage of M0. A total of 29 (87.9%) pts underwent surgery and were evaluable for efficacy endpoints. Surgery was not performed in 4 pts, 3 of whom were managed non-operatively (1 pt had progressive disease). MPR and pCR rates were 89.7% and 62.1%, respectively (Table). Any-grade and grade ≥3 TIS-related adverse events (TRAEs) were reported in 20 (60.6%) and 1 (3.0%) pts, respectively. Two (6.1%) pts experienced serious TRAEs; no TRAEs led to death or surgery cancellation. One pt (3.0%) experienced a TRAE (grade 2 hypothyroidism) leading to surgery delay. No grade ≥3 or serious TIS-related surgery-relevant adverse events were reported. Immune-mediated adverse events were reported in 10 (30.3%) pts (all grade 1-2). Conclusions: Neoadjuvant TIS was associated with high MPR and pCR rates and an acceptable safety profile, and did not compromise surgery in pts with resectable MSI-H/dMMR CRC. Clinical trial information: NCT05116085 . [Table: see text]
Neoadjuvant toripalimab plus chemotherapy followed by concurrent chemoradiotherapy in locally advanced esophageal squamous cell carcinoma (GASTO 1071).
Authors: Qiu Bo , Liu FangJie , Wang DaQuan , Luo QiaoTing , Wu YingJia , Guo JinYu , Zou YingYi , Rong YuMing , Luo GuangYu , Liu Hui
Published: June 2024

4077

Background: The combination of immune checkpoint inhibitor and concurrent chemoradiotherapy (CCRT) has been under investigation in patients with unresectable, locally advanced esophageal squamous cell carcinoma (ESCC). We explored the efficacy and safety of neoadjuvant toripalimab plus chemotherapy followed by CCRT in patients with locally advanced ESCC. Methods: This phase II, non-randomized, 2-cohort study enrolled patients with unresectable, stage T1-4N0-3M0-1 ESCC (M1 only includes patients with lymph node metastasis in the supraclavicular region). All patients were aged 18–80 years with an Eastern Cooperative Oncology Group performance status of 0–1. Patients in both cohorts received neoadjuvant therapy comprised of paclitaxel-albumin, nedaplatin and toripalimab 240 mg every 3 weeks, for 2 cycles, followed by CCRT (total dose 60Gy in cohort A, 50 Gy in cohort B, combined with oral capecitabine). The primary endpoint was progression-free survival (PFS) from enrollment. The trial is registered with ClinicalTrials.gov, NCT04844385. Results: Between February 26, 2021, and June 20, 2023, a total of 63 patients were enrolled in cohort A (54 men [85.7%]; median [interquartile range] age, 63 [58-65] years; 57 [90.5%] patients had stage III to IVB disease), and 61 patients were enrolled in cohort B (43 men [70.5%]; median [interquartile range] age, 65 [57-69] years; 52 [85.2%] patients had stage III to IVB disease). The objective response rate assessed 2 months after CCRT was 93.7% in cohort A and 93.4% in cohort B. At data cutoff (January 31, 2024), the median (range) follow-up duration was 31.3 (2.5-47.1) months in cohort A, and 17.0 (5.7-38.7) months in cohort B. The 12-month and 18-month PFS rates were 78.3%, 64.4% in cohort A, and 75.7%, 63.6% in cohort B. Median PFS was not reached in either cohort. Locoregional recurrence was observed in 19.0% (12/63) of patients in cohort A, and 24.6% (15/61) of patients in cohort B. Distant metastasis was observed in 12.7% (8/63) of patients in cohort A, and 3.3% (2/61) of patients in cohort B. Grade 3 and 5 pneumonitis occurred in 3.2% (2/63) and 1.6% (1/63) in cohort A, respectively, while no grade 3+ pneumonitis occurred in cohort B. Treatment-related esophageal fistula occurred in 1.6% (1/63) in cohort A and 1.6% (1/61) in cohort B. Conclusions: Neoadjuvant toripalimab plus chemotherapy followed by definitive CCRT demonstrated promising efficacy and acceptable toxicity in patients with locally advanced ESCC. Further study is warranted to confirm this conclusion. Clinical trial information: NCT04844385 .
Adjuvant mFOLFIRINOX (mFFX) for resected pancreatic cancer (PC): Long term clinical and genomic outcomes.
Authors: Keane Fergus , Moss Drew , O'Connor Catherine A , Perry Maria , Chou Joanne F. , Crowley Fionnuala , Saxena Parima , Chan Amelia , Park Wungki , Varghese Anna M. , Yu Kenneth H. , Capanu Marinela , Kingham T. Peter , D'Angelica Michael Ian , Balachandran Vinod P. , Jarnagin William R. , Wei Alice C , Soares Kevin , Balogun Fiyinfolu , O'Reilly Eileen M.
Published: June 2024

4170

Background: Adjuvant chemotherapy with mFFX is the standard for pts with ECOG 0-1 (1) after pancreatectomy for resectable PC. Herein, we report long-term survival data on an expanded cohort and present comprehensive genomic analyses. Methods: Pts with resected PC who received >1 dose of adjuvant mFFX identified from institutional databases. Primary endpoints: Recurrence Free Survival (mRFS) and Overall Survival (mOS) calculated from start of treatment until recurrence or death. Key secondary endpoints: clinical factors, genomic descriptors ( KRAS status, whole genome doubling (WGD), and homologous recombination deficiency (HRD)) associated with outcome. Kaplan-Meier method used to estimate RFS and OS. Univariate Cox proportional hazards model correlated clinico-genomic characteristics with RFS and OS. Results: N=147 identified between 01/2015-01/2022. Median age: 67 years; N= 22 (15%) > 75 years. Several prognostically unfavorable groups; N=52 (36%) stage III disease/ N2 nodal status; N=115 (78%) lymphovascular invasion (LVI); N=133 (90%) perineural invasion (PNI). Median time from surgery to start mFFX: 1.78m (IQR; 1.45, 2.12). Median CA 19-9 at start mFFX: 21 (range 0-1,124). N=124 (84%) pts completed 12 doses mFFX (+/- 12 doses oxaliplatin). N=98 pts (67%) stopped oxaliplatin early for neuropathy. With the median follow up 35.1m (range 5.1, 73.0), mRFS 27m (95% CI 20, 39) and OS not reached (NR). For >75 cohort, mRFS 12m (95% CI 9.6, NR) and mOS 30m (95% CI 19, NR). mFFX started <8 weeks from resection associated with improved RFS (HR 0.62; 95% CI 0.41, 0.96; p= 0.033) and OS (HR 0.53; 95% CI 0.3, 0.94; p= 0.030). T3 tumors associated with worse RFS (HR 2.82, 95% CI 1.28, 6.20; p=0.010) and OS (HR 5.10, 95% CI 1.45, 18; p=0.011). Genomic variables summarized (Table). KRASmutation (+), WGD (+), and higher KRAS CNV trended to shorter RFS and OS; statistical significance limited by small subgroups. HRD status did not confer differences in OS. Conclusions: Adjuvant mFFX is an effective therapy and results in long-term OS outcome in resected PC in a non-trial setting, including for pts >75 years. Early initiation of adjuvant mFFX may optimize outcome. Trends observed for improved outcome in select genomic subsets, which require large-scale validation. 1. Conroy, JAMA Onc, 2022. [Table: see text]
Radiomic survival prediction with liver metastases in colorectal cancer.
Authors: Park Inae , Lee Misuk , Shivakumar Jeevan , Park Sungjae
Published: June 2024

e15584

Background: The survival outcome of colorectal cancer depends upon staging and the presence of metastases. Nonetheless, there isn’t a reliable prediction model for overall survival (OS) specifically tailored to patients with colorectal cancer who have liver metastases. Consequently, this study aims to find radiomic features that can be utilized to predict OS of colorectal cancer with liver metastases. Methods: We utilized the Colorectal Liver Metastases data set in The Cancer Imaging Archive (TCIA). Overall, 197 patients with colorectal cancer metastatic to the liver were identified. Semi-automatic segmentation of liver metastases was used to extract radiomic features including Gray-Level Co-occurrence (glcm), Gray-Level Run Length Matrix (glrlm), Gray-Level Size Zone Matrix (glszm), Gray-Level Dependence Matrix (gldm), and Neighborhood Gray-Tone Difference Matrix (ngtdm). 3D Slicer was used to extract radiomic features. We tested a Cox proportional hazards model in each radiomics feature to predict OS. Results: Total 107 radiomic features were extracted from pre-segmented liver metastases on patients’ Computed Tomography images. Among them, original shape sphericity, original glcm correlation, original gldm DependenceEntropy, and original glrlm RunEntropy were statistically significant for the prediction of OS, with a hazard ratio of -2.16 (CI 0.01-0.92; p value 0.04), 1.54 (CI 1.5-14.0; p value 0.006), 0.51 (CI 1.0-2.5; p value 0.02), and 0.52 (CI 1.0-2.6; p value 0.03), respectively. Conclusions: Our data analysis indicates crucial radiomic features that hold promise for predicting the clinical outcome of patients with colorectal cancer who have liver metastases. Future research with a larger sample size is warranted for the external validation of our results.
A phase 1 trial evaluating the safety, tolerability, PK, and preliminary efficacy of QTX3034, an oral G12D-preferring multi-KRAS inhibitor, in patients with solid tumors with KRASG12D mutation.
Authors: Patnaik Amita , Pelster Meredith , Hong David S. , Strickler John H , Garrido-Laguna Ignacio , Aguirre Andrew , Curran Dominic , Woo Tina , Spira Alexander I.
Published: June 2024

TPS3172

Background: KRAS is one of the most mutated driver oncogenes across solid tumors, and KRAS G12D missense mutations have high prevalence in pancreatic, colorectal (CRC), and endometrial cancers. QTX3034 is a highly-selective, non-covalent, orally bioavailable, multi-KRAS inhibitor with potent activity across several KRAS variants, particularly G12D. QTX3034 binds to GDP-bound forms of mutant and wild-type KRAS with (sub)nanomolar affinities, allosterically inhibiting its conversion to the active state. QTX3034 inhibits KRAS signaling in in vitro studies and displays synergy with EGFR inhibitors. In vivo evaluation of QTX3034 resulted in significant tumor growth inhibition across various tumor models, with tumor regressions observed in 100% of animals in both HPAC pancreatic and GP2D colorectal KRAS G12D xenograft models. QTX3034 exhibits brain penetration in preclinical studies, including an orthotopic model of intracranial efficacy. This clinical trial is now enrolling patients with advanced solid tumors harboring a KRASG12D mutation. Methods: This is a first-in-human, multicenter, open-label phase 1 study in adult patients with advanced solid tumors with KRASG12D mutations, without prior direct KRAS inhibitor treatment (NCT06227377). The primary objectives are to evaluate the safety and tolerability and to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of QTX3034 alone, and in combination with cetuximab. Secondary objectives are characterization of the PK profile and preliminary antitumor activity. Part 1 consists of two dose-escalation arms: QTX3034 monotherapy (advanced solid tumors) and QTX3034 plus cetuximab (CRC) and will enroll 3-4 subjects per cohort in a Bayesian Logistic Regression Model (BLRM) design. QTX3034 will be administered orally in 21-day cycles until disease progression, intolerable toxicity, or withdrawal from treatment. Exploratory paired biopsies will be collected in Cycle 2 in a group of patients in the dose-escalation phase. Serial ctDNA will be collected in all patients. Following identification of a RP2D, QTX3034 will be evaluated in dose-expansion cohorts of up to 30 patients with various KRASG12D mutated tumor types to determine preliminary activity: pancreatic cancer, CRC, non-small cell lung cancer and endometrial cancer. To further optimize the recommended dose, patients will be randomized between two dose levels in the pancreatic cancer cohort. QTX3034 plus cetuximab will be explored following identification of a recommended combination dose in patients with CRC. Clinical trial information: NCT06227377 .
Care for Language
Authors: Barry Annabel
Published: June 2024

This interview discusses how Bonnie Honig’s theorization of “the ordinary” has changed throughout her career, the importance of care for language in feminist thought, and Honig’s own practices of linguistic attention as an agonistic close reader of artistic and political texts alike.
Keyhole Fenestration for Cerebrospinal Fluid Leaks in the Thoracic Spine: Quantification of Bone Removal and Microsurgical Anatomy
Authors: Volz Florian , Doria-Medina Roberto , Fung Christian , Wolf Katharina , El Rahal Amir , Lützen Niklas , Urbach Horst , Loidl Theresa Bettina , Hubbe Ulrich , Klingler Jan-Helge , Beck Jürgen
Published: June 2024

BACKGROUND AND OBJECTIVE:

A safe working trajectory is mandatory for spinal pathologies, especially in the midline, anterior to the spinal cord. For thoracic cerebrospinal fluid (CSF) leaks, we developed a minimally invasive keyhole fenestration. This study investigates the necessary bone removal for sufficient exposure of different leak types particularly regarding weight-bearing structures.

METHODS:

In this retrospective case series between January 2022 and June 2023, the volume of bone resection and the axial and sagittal diameter of hemilamina defects after closure through keyhole fenestration were quantified. The involvement of facet joints and pedicles was qualitatively rated. Demographic (age, sex, body mass index, leak type) and surgical data (blood loss, surgery time, discharge after surgery) and complications were analyzed.

RESULTS:

Thirty-three patients with 34 approaches were included. The volume of resected bone was 1.5 cm3, and the diameter of the hemilamina defect was 17.8 mm in the sagittal and 15.1 mm in the axial plane. Facet joints were uninvolved in 24% and partly resected in 74%, and one facet joint was resected completely. Pedicles remained intact in 71% and were minimally involved in 29%. The median surgery time was 93 minutes, blood loss was 45 mL, and discharge was 4 days after surgery. Three patients (9%) needed revision surgery. No relevant and persisting morbidity occurred. Within the median follow-up period of 10 months, no stabilizing surgery was necessary. No permanent neurological deficit occurred.

CONCLUSION:

The keyhole fenestration leaves weight-bearing structures like facet joints and pedicles intact in most cases. The limited, penny-sized bone resection is sufficient to reach and close thoracic CSF leaks Type 1, 2, and 3 from the anterior midline to the ganglion. For experienced centers, it is a universal minimally invasive approach for treating all CSF leaks.
Normotensive metabolic syndrome in Transient Receptor Potential Canonical Channel type 1 Trpc1−/− mice.
Authors: Atkins Richard Matthew , Pantalia Meghan , Skaggs Christopher , Lau Alexander Ku , Mahmood Muhammad Bilal , Anwar Muhammad Mubeen , Barron Lindsay , Eby Bonnie , Khan Usman , Tsiokas Leo , Lau Kai
Published: June 2024

Metabolic syndrome has become a global epidemic, affecting all developed countries and communities with growing economies. Worldwide, increasing efforts have been directed at curbing this growing problem. Mice deleted of the gene encoding Type 1 Transient Receptor Potential Canonical Channel (Trpc1) were found to weigh heavier than controls. They had fasting hyperglycemia and impaired glucose tolerance compared with wild-type controls. Beyond 1 year of age, plasma triglyceride level in Trpc1−/− mice was elevated. Plasma cholesterol levels tended to be higher than in controls. The livers of Trpc1−/− mice were heavier, richer in triglyceride, and more echogenic than those of controls on ultrasound evaluation. Hematocrit was lower in Trpc1−/− mice of both genders beginning at the second to third months of age in the absence of bleeding or hemolysis. Measured by the indirect tail-cuff method or by the direct arterial cannulation, blood pressures in null mice were lower than controls. We conclude that TRPC1 gene regulates body metabolism and that except for hypertension, phenotypes of mice after deletion of the Trpc1 gene resemble mice with metabolic syndrome, suggesting that this could be a good experimental model for future investigation of the pathogenesis and management of this disorder.
Flavonols do not affect aphid load in green or senescing birch leaves but coincide with a decrease in Photosystem II functionality
Authors: Mattila Heta , Khorobrykh Sergey , Tyystjärvi Esa
Published: June 2024

Instead of red anthocyanins, birches synthesise colourless (to human eye), UV-absorbing flavonols during autumn senescence. To test if flavonols protect against insects, and if leaves with high or low amounts of flavonols differ in their photosynthetic functions, aphid-free and aphid-infested green and senescing birch leaves were collected from outdoor-grown trees and analysed. Photosynthetic parameters were greatly affected by the leaf chlorophyll content (i.e. the phase of senescence). Photochemical quenching and the amount of functional Photosystem I decreased linearly with chlorophyll content, while FV/FM (Photosystem II functionality) decreased strongly only at the end of senescence. Non-photochemical quenching of excitation energy (NPQ) increased towards the end of senescence. However, no significant differences in the total flavonol amounts, nor in individual flavonol species, were found between aphid-free and aphid-infested leaves, suggesting that flavonols play no role in defence against aphid herbivory. Interestingly, both green and senescing leaves with a high flavonol content showed low FV/FM values. High flavonol content slowed down PSII photoinhibition and improved recovery, but only in green leaves. Previously, we proposed that anthocyanins provide an additional sink for photosynthates at the nitrogen resorption phase during autumn senescence, and the present data may suggest that flavonol synthesis plays a similar role.
Insights into the Beginnings and Glory of Romanian Gerontology
Authors: Baran Dana
Published: June 2024

Romanian medicine has made significant early contributions to modern gerontology and geriatrics. Understanding, integrating and combating old age was in keeping not only with ancient mythology and old Romanian fairy-tales, but also with the scientific approaches to the art of prolonging life, or macrobiotics, which emerged in the 19th century. In the 20th century, several Romanian doctors focused on gerontology and geriatrics, a research area directly related with the progress of neurology, endocrinology and physiology. Professors Gheorghe Marinescu, Constantin I. Parhon and Ana Aslan, along with Grigore Benetato, all members of the Romanian Academy, as well as Dr. Dimu Kotsovsky were among these scientists interested in age study and management. Institutes, publications and medico-social establishments were designed for this purpose. Today, Romania is striving to revitalise its rich tradition of gerontology and geriatrics in alignment with current international standards.
Evaluation of comparative efficacy of Celastrus paniculatus (Jyotishmati) capsule versus sertraline capsule in the management of Chittodvega (generalized anxiety disorder): protocol for a randomized controlled trial
Authors: Gamne Reeya , Misar Sadhana , Rai Mayank
Published: June 2024

Background Generalized anxiety disorder (GAD)(Chittodvega)is one among many types of mental disorders explained in Ayurveda. It can be defined as aChitta(mind) +Udvega(anxiety)=Chittodvega- Anxious status of a mind.Celastrus paniculatusalso known asJyotishmati.stimulates and improves the digestive fire and metabolism at a cellular level (Jatharagni and Majja dhatwagni).It can be correlated to GAD. GAD is characterized by feelings of threat, restlessness, irritability, sleep disturbance, and tension, and symptoms such as palpitations, dry mouth, and sweating. It affects women more frequently than men and prevalence rates are high in midlife (prevalence in females over age 35: 10%) and older subjects. In modern medicine the first-line psychological and pharmaceutical treatments are selective serotonin reuptake inhibitors (SSRIs) like sertraline (SNRIs). Aim and objectives To evaluate the comparative efficacy ofJyotishmativersus sertraline in the management ofChittodvega.Methods In this randomized active controlled double blind equivalence trial a total of 70 patients will be enrolled and divided into two equal groups. Patients between 20–50 years age of either gender having symptoms ofChittodvegaand a Hamilton anxiety rating (HAM-A) scale score less than 24 (i.e., mild to moderate) will be selected for the study. In Group A, sertraline capsules 25 mg for first 7 days and then dose increased to 50 mg at bedtime for next 53 days and in Group BJyotishmatiCapsules 500 mg will be given twice a day after food with water for 60 days. Result and observation The patients will be assessed on the HAM-A scale, serum cortisol and WHO Quality of Life on day 0, 30, 60 and 90 and data will be analyzed using paired and unpaired t-tests for continuous variables and chi-square tests for categorical variables to evaluate whether treatments are equivalent. Trial registration CTRI No. REF/2023/07/069880 Date – 15/09/2023
Bilateral congenital muscular torticollis in infants, report of two cases
Authors: Öhman Anna
Published: June 2024

Background Congenital muscular torticollis (CMT) is a well-known diagnosis among physiotherapists specializing in pediatric care, especially when working with infants. However, knowledge of bilateral torticollis is limited. The purpose of this article was to describe how bilateral torticollis may present itself clinically. Case One infant with CMT with sternocleidomastoid tumor (SMT) on the right side, and some limitation in rotation towards the right side and in lateral flexion towards the left side, i.e, the muscle on the right side was shortened. While sitting with support, he tilted the head to the left and was stronger in the lateral flexors on the left side which fit well with a postural left-sided torticollis (PT). The other infant had bilateral muscular torticollis (MT), the sternocleidomastoid muscle thickened bilaterally, and both active and passive rotations were affected. The head was held in flexion, and active rotation was severely limited to both sides. For both cases the therapeutic interventions were to gain a normal range of motion (ROM) and a good posture of the head. Conclusions CMT can appear in different ways and may be bilateral. Both infants gained good ROM and better head position, however case I still needs some training. To gain more knowledge about bilateral CMT, we should follow these cases over a longer period of time. It is important to communicate and discuss our experiences with each other to understand rare cases of CMT.
Case Report: Surgical intervention of colo-pleural fistula secondary to colon diverticulosis with history of hernia diaphragmatica
Authors: Jeo Wifanto Saditya , Prihanda Suryaningprang Alldila Hendy , Setiawan Andre , Natasya Natasya , Christina Shintia
Published: June 2024

Abstract* Introduction Colopleural fistulas are rare and generally correspond to thoracic empyema alongside an acute abdomen. Early diagnosis and prompt treatment are essential to prevent recurrence of thoracic empyema. Case presentation An 18-year-old male was admitted to our hospital with dyspnea and abdominal pain. The patient had a history of a left diaphragmatic hernia repair. Physical examination revealed signs of left-sided pleural effusion and abdominal pain. Chest computed tomography (CT) revealed a left lung empyema with a suspected connection to the intra-abdominal cavity through the diaphragm. Colopleural fistula and diverticulosis were confirmed by colonoscopy. Subsequently, primary resection, transverse-descending anastomosis, and fistula suturing were performed, accompanied by empyema evacuation through thoracotomy and diverting colostomy. Clinical Discussion Colopleural fistula is an incredibly rare phenomenon that can result from diaphragmatic injury, malignancies, perforated diverticulosis, or colonic/pulmonary infections. The management of a colopleural fistula depends on anatomical, clinical, and other factors. Diverticulitis is usually treated using antibiotics and other conservative therapies. Diverticular disease usually requires surgery if there is perforation, progressive signs of sepsis or peritonitis, fistula, or failure of conservative treatment. A surgical procedure was performed in this case because of empyema arising from a colopleural fistula formation caused by diverticulosis. Conclusion Primary colon resection, colon anastomosis, fistula suturing, and decortication thoracotomy were shown to effectively treat colopleural fistula.
Metagenome quality metrics and taxonomical annotation visualization through the integration of MAGFlow and BIgMAG
Authors: Yepes-García Jeferyd , Falquet Laurent
Published: June 2024

Background Building Metagenome–Assembled Genomes (MAGs) from highly complex metagenomics datasets encompasses a series of steps covering from cleaning the sequences, assembling them to finally group them into bins. Along the process, multiple tools aimed to assess the quality and integrity of each MAG are implemented. Nonetheless, even when incorporated within end–to–end pipelines, the outputs of these pieces of software must be visualized and analyzed manually lacking integration in a complete framework. Methods We developed a Nextflow pipeline (MAGFlow) for estimating the quality of MAGs through a wide variety of approaches (BUSCO, CheckM2, GUNC and QUAST), as well as for annotating taxonomically the metagenomes using GTDB-Tk2. MAGFlow is coupled to a Python–Dash application (BIgMAG) that displays the concatenated outcomes from the tools included by MAGFlow, highlighting the most important metrics in a single interactive environment along with a comparison/clustering of the input data. Results By using MAGFlow/BIgMAG, the user will be able to benchmark the MAGs obtained through different workflows or establish the quality of the MAGs belonging to different samples following the divide and rule methodology. Conclusions MAGFlow/BIgMAG represents a unique tool that integrates state-of-the-art tools to study different quality metrics and extract visually as much information as possible from a wide range of genome features.
Incorporating basic periodontal screening into antenatal care services provided in Rwanda: A policy brief
Authors: Uwambaye Peace , Kanmodi Kehinde Kazeem
Published: June 2024

Background Preterm birth, which is child delivery before 37 weeks of pregnancy, is the primary cause of perinatal mortality worldwide. Preterm birth remains a major public health challenge in Rwanda, affecting approximately 13.8% of birth. The World Health Organization estimates that 15 million babies are born prematurely each year. While the association between periodontitis and preterm deliveries is increasingly recognized, little is known about this link in Rwanda. This policy brief aims to bridge this knowledge gap by presenting the findings of a recent study investigating the prevalence of periodontitis among pregnant women in Rwanda and its association with preterm deliveries. This policy brief also aims to inform and guide decision making towards incorporating periodontal screening into the antenatal care package in Rwanda. This has the potential to improve pregnancy outcomes and contribute to improved oral health in the future. Policy outcome and Implications Contemporary evidence has shown a six-fold increased risk of preterm delivery for women with periodontitis in Rwanda, with a concerningly high prevalence (60%) among pregnant women. Additionally, nurses working in antenatal clinics displayed insufficient knowledge about gum disease. Actionable recommendations The adoption of basic periodontal screening within existing antenatal care packages is recommended. This, coupled with nurse training and public awareness campaigns, can empower women and healthcare professionals to prioritize oral health for better pregnancy outcomes. Conclusions Integrating periodontal screening into antenatal care has the potential to significantly reduce preterm deliveries and contribute to a healthier future generation in Rwanda.
Proso włoskie (Setaria italica L.) – relikt czy skarb?
Authors: Plażuk Ewa , Mystkowska Iwona , Kosińska Beata , Dmitrowicz Aleksandra
Published: June 2024

Proso włoskie (Setaria italica L.) to jedna z najstarszych roślin uprawnych na świecie, której kultywację rozpoczęto około 10 tys. lat temu w Chinach. Z jego ziaren wytwarzano kaszę i mąkę, a z niej chleb. W dawnych czasach gatunek ten uprawiano w Europie i Azji. Dziś uprawiany jest głównie w Afryce oraz Azji, jako źródło pożywienia, a w USA przede wszystkim na paszę jako pastewna trawa (m.in. pokarm dla papug). W Polsce proso włoskie ma wartość reliktową i jest uprawiane w skansenach, np. na Ostrowie Lednickim wokół dawnej historycznej osady Słowian. Chociaż powierzchnia upraw prosa jest znacznie mniejsza niż pszenicy, ryżu i kukurydzy, które stanowią około 60% wszystkich światowych upraw, coraz częściej docenia się je w produkcji żywności dla ludzi i zwierząt. Ma ono bowiem korzystny skład odżywczy i dużą przydatność jako zdrowa żywność bezglutenowa o niskim indeksie glikemicznym, co nabiera znaczenia wobec narastających chorób cywilizacyjnych związanych z niewłaściwą dietą. Ze względu na łatwość przystosowywania się do trudnych warunków klimatycznych rośliny te należą do upraw wysoce odpornych na stres abiotyczny. Proso, oprócz pełnionej dotychczas roli podstawowego produktu żywnościowego w biednych społecznościach żyjących w marginalnych regionach rolniczych, w ostatnich latach zaczyna być pożywieniem cenionym przez mieszkańców miast zainteresowanych zdrową dietą – jako pożywny i zdrowy pokarm, będący alternatywą dla pszenicy zawierającej gluten. Na jego korzyść przemawia to, że w dobie dużej chemizacji rolnictwa uprawy te nie wymagają stosowania środków ochrony roślin, mogą więc stanowić składnik żywności ekologicznej, i jako zasoby genetyczne są ważne dla bezpieczeństwa żywnościowego.
Cuando no queda más por contar: eutanasia y suicidio asistido en el cine
Authors: Gómez Córdoba Ana Isabel , Pinto Bustamante Boris Julián , Luna Hernández María Camila , Ríos Samper Laura Vanesa , Catalani Silva Isabella , Arango Romero Helena , Garzón Luna Daniel Ignacio , Téllez Alarcón Manuela
Published: June 2024

El presente capítulo aborda, desde una perspectiva pluralista, las prácticas asistenciales eutanasia y suicidio asistido, en sus dimensiones histórica, filosófica, jurídica y médica. Se revisa la evolución normativa y jurídica de la despenalización de la eutanasia en Colombia, tanto para personas mayores de 18 años como para niños, niñas y adolescentes. El trabajo recoge diferentes perspectivas axiológicas y reconoce la controversia ética que estas prácticas originan, tanto en el nivel social como para los marcos deontológicos de las profesiones de la salud. No obstante, se reconocen estos procedimientos como posibilidades a las que personas, en uso de sus facultades mentales, pueden hacer uso para el logro de una muerte digna, si bien esta aspiración también se puede alcanzar por medio de otras posibilidades, como los cuidados paliativos. El trabajo utiliza diversas narrativas fílmicas como recurso didáctico que permite ejemplificar la complejidad moral de la eutanasia y el suicidio asistido en contextos culturales diferentes.
Seguro de cumplimiento de contratos estatales: reflexiones sobre el tratamiento legal y jurisprudencial
Authors: Mejía Martínez Carmenza
Published: June 2024

En el presente ensayo se hace un examen crítico del tratamiento dado por la jurisprudencia a algunos de esos temas, en particular respecto de i) si la noción de siniestro la constituye el solo hecho del incumplimiento o si la configura el acto administrativo proferido por la entidad estatal; ii) si la expedición de dicho acto administrativo comporta o no el ejercicio de una facultad excepcional de la Administración; iii) si la oportunidad para que la entidad contratante deba expedir el acto administrativo para hacer efectiva la garantía debe ser en vigencia de la póliza o dentro de los términos de prescripción del régimen mercantil; y iv) si la prescripción para la exigibilidad de la garantía corre desde la notificación del acto administrativo o desde el hecho material del incumplimiento.
Reviewing the transition from child to adult care: considerations for managers
Authors: Mahoney Nicholas , Freeth Heather , Michalski Antony , Malbon Katie , Tavaré Alison
Published: June 2024

The authors explain the National Confidential Enquiry into Patient Outcome and Death report and highlight the areas where healthcare managers can help clinicians facilitate the transition of children and young people with chronic health conditions into adult health services.
Controllable optical chirality of vortex beams via photonic jets
Authors: Shi Yiyu , Cui Zhiwei , Cao Xinyi , Liu Zhanfei , Zhao Wenjuan
Published: June 2024

Recent years have witnessed great interest in the optical chirality of vortex beams carrying orbital angular momentum (OAM). An interesting area of research is the control of such an optical chirality. In this work, we report a study of the controllable optical chirality of vortex beams via photonic jets. Within the framework of the generalized Lorenz–Mie theory (GLMT), we present the analytical expressions for describing the electromagnetic fields of the photonic jets formed on the shadow side of the micro-sized dielectric spheres illuminated by Laguerre–Gaussian (LG) vortex beams. The optical chirality of the vortex beams focused in the near-field area of the photonic jets is numerically simulated. It is revealed that the optical chirality of the vortex beams is drastically enhanced via photonic jets. Moreover, the optical chirality of the vortex beams focused in the near-field area of the photonic jets can be controlled by choosing the radius and refractive index of the dielectric sphere. Such controllable optical chirality is expected to be applicable in chiral manipulation, detection, and recognition.
Enhanced performance of amplified spontaneous emission in Dion-Jacobson phase quasi-2D perovskite by facilitating carrier co-radiation
Authors: Zhang Yuan , Dong Zhiwei , Guo Xiwei , Hu Yongsheng , Zhang Zhibin , Deng Yanyan , Zhang Yong , Men Zhuowu , Geng Chong , Wang Yulei , Chen Zhaodong , Jiang Yugang , Song Li , Xia Yuanqin
Published: June 2024

Dion-Jacobson (DJ) structured quasi-2D perovskites are promising candidates for new generation gain medium due to their excellent photoelectric performance, super environmental, and structure stability. The isolated carrier recombination with inhomogeneous mixed phase is detrimental in enhancing amplified spontaneous emission (ASE) of optically pumped DJ phase quasi-2D perovskites lasers. Here, in 1.3-propanediamine (PDA)-based DJ perovskites, the carrier dynamic behavior from the pristine sample to the Cremophor EL (Cre EL) treated sample is unraveled. Remarkably, the Cre EL treated sample displays a well-proportioned large n domain distribution, resulting in an increased radiation-state density and hence enhancing collaboration emitting between carriers. The improved collaboration emitting promotes carriers' fast relay radiation, resulting in a higher ASE performance with a threshold reduced from 11.7 to 4.8μJ/cm2, optical gain coefficient increased from 775 to 1559 cm-1 and degree-of-polarization (DOP) improved from 0.59 to 0.98. Our findings suggest that the development of DJ structured quasi-2D perovskite laser gain medium should target facilitating fast carrier co-radiation recombination.
CTIS spectral image reconstruction technology based on slit-scanning architecture
Authors: Zhou Pengwei , Lv Yangfan , Zheng Yuqi , Zhou Jiamin , Chen Liang
Published: June 2024

The computed tomography imaging spectrometer (CTIS) is a snapshot imaging spectrometer, excelling in dynamic detection tasks. It can capture two-dimensional spatial information and spectrally compressed information of a target within a single exposure time. However, traditional CTIS image reconstruction algorithms suffer from missing-cone problem, which reduces the accuracy of spectral reconstruction. In recent years, deep learning has been applied to CTIS spectral image reconstruction, significantly improving spectral reconstruction accuracy compared to traditional algorithms. However, due to the missing-cone problem, it is difficult to accurately recover the truth of spectral data cube in the real scene. Currently, most CTIS neural network reconstruction models are trained using simulated datasets of spectral data cubes and diffractive images. Because these data differ significantly from real data under actual application conditions, the established models may not be effectively applicable to real-world scenes. Therefore, we propose a new CTIS system based on slit-scanning architecture utilizing an adjustable slit aperture to obtain the real spectral data cube of the target while maintaining the simplicity of the CTIS structure. By limiting the field of view (FOV) through the slit, the area of diffraction overlap can be reduced, thereby enhancing the accuracy of CTIS spectral reconstruction using the expectation-maximization (EM) algorithm. This architecture allows us to obtain accurate spectral cubes that match the CTIS diffractive image of real-world scenes, providing a real dataset for training the reconstruction network. A prototype has been built to demonstrate the feasibility of our proposed solution. Furthermore, we also constructed a residual network based on multi-scale and attention mechanism. This network is trained using a combination of simulated and real spectral imaging data. Compared to the reconstruction performance of the EM algorithm and convolutional neural networks, our approach demonstrates superior spectral reconstruction accuracy, validating the importance of real spectral data in CTIS spectral reconstruction tasks.
The clock-like accumulation of germline and somatic mutations can arise from the interplay of DNA damage and repair
Authors: Spisak Natanael , de Manuel Marc , Milligan William , Sella Guy , Przeworski Molly
Published: June 2024

The rates at which mutations accumulate across human cell types vary. To identify causes of this variation, mutations are often decomposed into a combination of the single-base substitution (SBS) “signatures” observed in germline, soma, and tumors, with the idea that each signature corresponds to one or a small number of underlying mutagenic processes. Two such signatures turn out to be ubiquitous across cell types: SBS signature 1, which consists primarily of transitions at methylated CpG sites thought to be caused by spontaneous deamination, and the more diffuse SBS signature 5, which is of unknown etiology. In cancers, the number of mutations attributed to these 2 signatures accumulates linearly with age of diagnosis, and thus the signatures have been termed “clock-like.” To better understand this clock-like behavior, we develop a mathematical model that includes DNA replication errors, unrepaired damage, and damage repaired incorrectly. We show that mutational signatures can exhibit clock-like behavior because cell divisions occur at a constant rate and/or because damage rates remain constant over time, and that these distinct sources can be teased apart by comparing cell lineages that divide at different rates. With this goal in mind, we analyze the rate of accumulation of mutations in multiple cell types, including soma as well as male and female germline. We find no detectable increase in SBS signature 1 mutations in neurons and only a very weak increase in mutations assigned to the female germline, but a significant increase with time in rapidly dividing cells, suggesting that SBS signature 1 is driven by rounds of DNA replication occurring at a relatively fixed rate. In contrast, SBS signature 5 increases with time in all cell types, including postmitotic ones, indicating that it accumulates independently of cell divisions; this observation points to errors in DNA repair as the key underlying mechanism. Thus, the two “clock-like” signatures observed across cell types likely have distinct origins, one set by rates of cell division, the other by damage rates.