bluuebunny/crossref_metadata_2025 huggingface dataset:
An HD‐Zip III transcription factor, BjPHVa, negatively regulates non‐glandular trichome formation in Brassica juncea
Authors: Zhou Yulan , Wang Mingyun , Liu Yutong , Li Zhangping , Hu Zhongyuan , Zhang Mingfang , Yang Jinghua
Published: October 2024

Trichomes are specialized structures derived from epidermal cells. Non‐glandular trichomes primarily protect plants from herbivores and intense ultraviolet radiation by acting as a physical barrier. Recent research has highlighted the importance of homeodomain leucine zipper (HD‐Zip) IV transcription factors (TFs) in promoting trichome development. In this study, an HD‐Zip III TF called PHAVOLUTA (BjPHVa) was identified as a negative regulator of non‐glandular trichome initiation in Brassica juncea. Genome editing of BjPHVa resulted in a significant increase in trichome number in B. juncea. Co‐expression networks revealed a strong association between trichome development and the HD‐Zip family, which was supported by transcriptomic analysis findings. An R2R3‐MYB TF, BjGL1a, a key regulator of trichome development, was found to be associated with BjPHVa‐regulated trichome development. Knockdown of BjGL1a expression resulted in reduced trichome number in B. juncea. BjPHVa was observed to interact directly with BjGL1a while binding to the BjGL1a promoter, resulting in the inhibition of BjGL1a transcription. These results provide new insights into the identification of regulators involved in trichome development and offer new opportunities to enhance resistance to predicted stresses through genome editing targeting PHVa within Brassicaceae.
Evidence for the translocation of fixed N in the N2‐fixing lichen Stereocaulon vesuvianum
Authors: Crittenden Peter D. , Thornton Barry
Published: October 2024

The fruticose lichen Stereocaulon vesuvianum is among the most abundant and widespread lichens in upland Britain. It typically produces cephalodia (nodules) that contain the cyanobacterium Stigonema, which can fix atmospheric nitrogen. However, over much of England, Wales, and southern Scotland S. vesuvianum no longer produces cephalodia and does not fix nitrogen, a morphological change linked to elevated atmospheric nitrogen deposition. This provided a unique opportunity to compare the 15N natural abundance signatures in N2‐fixing and non‐N2‐fixing lichen populations, keeping in mind that fixed nitrogen has a 15N content close to that of atmospheric N2 while, in comparison, several components of atmospheric combined N (e.g. nitrate and ammonium in precipitation) tend to be 15N depleted. We found that in N2‐fixing samples, there was a steep gradient in 15N relative abundance in the terminal 15 mm of thallus branches (pseudopodetia), changing from 15N depleted tissues at 10–15 mm below the tips to values close to that of atmospheric N2 at the apices while in non‐N2‐fixing samples thallus branches were uniformly 15N depleted. The 15N gradient in N2‐fixing material could not be explained by the presence of cephalodia since these are more abundant towards branch bases. The data provide the first evidence in lichens of translocation of recently fixed N to sink regions of active growth and production of asexual reproductive propagules, bringing lichens into line with N source‐sink relationships in N2‐fixing plant symbioses.
A safety comparison of heparin and argatroban anticoagulation in veno‐venous extracorporeal membrane oxygenation with a focus on bleeding
Authors: Burša Filip , Máca Jan , Sagan Jiří , Sklienka Peter , Němcová Simona , Kučerová Zuzana , Romanová Tereza , Jor Ondřej , Kondé Adéla , Janošek Jaroslav , Frelich Michal
Published: October 2024

Background

Anticoagulation during extracorporeal membrane oxygenation (ECMO) might still lead to severe bleeding complications. Heparin is the most frequently used anticoagulant, but novel drugs could be promising. Argatroban is a new alternative to heparin. To date, no robust studies have confirmed the clear superiority of argatroban (AG) over heparin, although it has some advantages and may be safer.

Study Design and Methods

An observational study was conducted in all adult veno‐venous ECMO patients with COVID‐19‐associated acute respiratory distress syndrome admitted to the University Hospital Ostrava (n = 63). They were anticoagulated with heparin in the first period and with AG in the second period, targeting the same activated partial thromboplastin time (aPTT; 45–60 s). Bleeding complications requiring transfusion and life‐threatening bleeding events were evaluated. The primary objective was to compare heparin and AG in terms of bleeding, transfusion requirements and mortality‐related bleeding.

Results

The total time on ECMO per patient was 16 days with an in‐hospital mortality of 55.6%. The red blood cell consumption in the AG group (median 2.7 transfusions/week) was significantly lower than in the heparin group (median 4.2 transfusions/week, p = 0.011). Life‐threatening bleeding complications were higher in the heparin group compared to the AG group (35.7% vs. 10.2%, p = 0.035), and mortality‐related bleeding complications were also higher in the heparin group (21.4% vs. 2.0%, p = 0.032).

Discussion

Argatroban is an interesting alternative to heparin with less bleeding, less need for red blood cell transfusions and improved safety of ECMO with less mortality‐related bleeding.
RICELONG GRAIN 3 delays dark‐induced senescence by downregulating abscisic acid signaling and upregulating reactive oxygen species scavenging activity
Authors: Lim Chaemyeong , Kang Kiyoon , Lim Jisun , Lee Haeun , Cho Sung‐Hwan , Paek Nam‐Chon
Published: October 2024

Leaf senescence is a complex developmental process influenced by abscisic acid (ABA) and reactive oxygen species (ROS), both of which increase during senescence. Understanding the regulatory mechanisms of leaf senescence can provide insights into enhancing crop yield and stress tolerance. In this study, we aimed to elucidate the role and mechanisms of rice (Oryza sativa) LONG GRAIN 3 (OsLG3), an APETALA2/ETHYLENE RESPONSIVE FACTOR (AP2/ERF) transcription factor, in orchestrating dark‐induced leaf senescence. The transcript levels of OsLG3 gradually increased during dark‐induced and natural senescence. Transgenic plants overexpressing OsLG3 exhibited delayed senescence, whereas CRISPR/Cas9‐mediated oslg3 mutants exhibited accelerated leaf senescence. OsLG3 overexpression suppressed senescence‐induced ABA signaling by downregulating OsABF4 (an ABA‐signaling‐related gene) and reduced ROS accumulation by enhancing catalase activity through upregulation of OsCATC. In vivo and in vitro binding assays demonstrated that OsLG3 downregulated OsABF4 and upregulated OsCATC by binding directly to their promoter regions. These results demonstrate the critical role of OsLG3 in fine‐tuning leaf senescence progression by suppressing ABA‐mediated signaling while simultaneously activating ROS‐scavenging mechanisms. These findings suggest that OsLG3 could be targeted to enhance crop resilience and longevity.
Hypoechoic ultrasonographic findings in the patellar ligaments are common in riding and trotting horses in training (116 cases)
Authors: Law Ellen , Wright Linda , Uhlhorn Margareta , Hernlund Elin , Nilemo Carolina , Rhodin Marie
Published: October 2024

Patellar ligament (PL) injuries are increasingly being reported in horses, but few studies have described the normal PL ultrasonographic appearance in horses. The aims of this prospective observational study were to describe the ultrasonographic appearance of the PLs and infrapatellar fat pad in a population of horses in training and to relate the ultrasonographic findings to objectively measured movement asymmetry. B‐mode and color Doppler ultrasonographic examination of the PLs and infrapatellar fat pad in both hind limbs and objective gait analyses were performed on the 116 riding and trotting horses included in the study. The association between ultrasonographic findings, horse age, and movement asymmetry during the trot was then investigated.

Distinct or diffuse hypoechoic regions were commonly found in the intermediate PL (24/116; 20.7%), especially in the caudal aspect of the mid‐third of the ligament. The infrapatellar fat pad had a hypoechoic striated appearance in all horses except one, in which it was hyperechoic. No association was found between ultrasonographic findings in the PLs and infrapatellar fat pad and lameness. It is important to recognize that there is biological variation in PL appearance, which may or may not be associated with pain in this area, therefore emphasizing the use of local analgesia to determine the location of the lameness.
A randomized comparison of an adhesive gelatin sponge and a plain collagen sponge for hemostatic control during canine liver surgery
Authors: Anderson Thomas S. , Hattersley Rachel D. , Demetriou Jackie L.
Published: October 2024

Objective

To compare the effectiveness of a modified surface gelatin sponge to a plain collagen sponge for hemostasis of parenchymal hepatic bleeding.

Study design

Prospective, randomized trial of two hemostatic agents.

Animals

A total of 45 dogs undergoing elective liver surgery were randomly allocated into two groups: 22 in the adhesive gelatin (AG) group and 23 in the plain collagen (PC) group. A total of 20 patients per group underwent liver biopsy to create a uniformly sized bleeding surface, with the remaining patients (AG = 2, PC = 3) undergoing liver lobectomy.

Methods

Evaluation of hemostatic effectiveness and tissue adhesion of each sponge type was performed by the operating surgeon using structured scoring systems. Hemostatic parameters were primarily evaluated at the liver biopsy site to maintain homogeneity of bleeding surface size.

Results

For the liver biopsy group (n = 40), 5 min after hemostatic sponge application, 10/20 dogs were bleeding in the PC group, compared to 2/20 in AG group (p = .0138). The PC bleeding was significantly higher than AG across the 3 to 6 min evaluation period (p < .001). When surgeons tested the adhesion of the sponge across the whole cohort (n = 45), AG scored 2 (of 3) against 1 for PC (p < .001). In group PC, 5/23 sponges dislodged during abdominal lavage and preparations for closure and had to be replaced due to recurrence of bleeding, compared with no AG sponges dislodging (p = .042). There were no further complications related to the use of either sponge.

Conclusion

In the dogs with hepatic parenchymal incision, use of an adhesive gelatin sponge improved intraoperative attachment and haemostatic effectiveness, compared to a collagen sponge.

Clinical significance

Based on our clinical experience in these cases, adhesive gelatin sponges could be considered an effective option when selecting a hemostatic agent for liver surgery in dogs.
Residual diabetic foot osteomyelitis after surgery leads to poor clinical outcomes: A systematic review and meta‐analysis
Authors: Reyes Mario C. , Suludere Mehmet A. , Tarricone Arthur N. , Sajjad Tehreem , Coye Tyler L. , Sideman Matthew J. , Lavery Lawrence A.
Published: October 2024

The aim of this meta‐analysis is to compare the clinical outcomes in patients with and without residual osteomyelitis (ROM) after surgical bone resection for diabetic foot osteomyelitis (DFO). We completed a systematic literature search using PubMed, Scopus, and Embase using keywords DFO, Residual OM (ROM), and positive bone margins. The study outcomes included wound healing, antibiotic duration, amputation, and re‐infection. Five hundred and thirty patients were included in the analysis; 319 had no residual osteomyelitis (NROM), and 211 had ROM. There was not a significant difference in the proportion of wounds that healed 0.6 (p = 0.1, 95% confidence intervals [95% CI] 0.3–1.3). The risk of infection was 2.0 times higher (OR = 2.0, p = 0.02, 95% CI 1.1–3.4), and the risk of amputation was 4.3 times higher (OR = 4.3, p = 0.0001, 95% CI 2.4–7.6) in patients with ROM. Patients with ROM received antibiotics significantly longer. The mean difference was 16.3 days (p = 0.02, 95% CI 11.1–21.1).
Building Energy Savings and Power Output Augmentation of Roof Mounted Photovoltaic Using Co-Located Rooftop Reflectors
Authors: Alasadi Habeeb , Choi Jun-Ki , Mulford Rydge B.
Published: October 2024

Photovoltaic (PV) panels installed on building rooftops yield a positive influence on the thermal performance of the building due to the shading of the PV panels, decreasing cooling loads while causing a smaller increase in heating loads. Additionally, the electrical power output of PV panels has been shown to be increased by including reflectors between PV rows, concentrating the solar flux onto the active portion of the panels. When implemented into the spaces between the rows of a roof-mounted PV array, reflectors might further improve the positive thermal effects of rooftop installed PV arrays. This work focuses on predicting rooftop heat flux and temperature for a building rooftop equipped with PV panels and reflectors. The saved energy load, additional energy load, PV power output, rooftop heat flux, and the utility factor (ratio of positive building energy impacts to negative building energy impacts) are reported parametrically for variations in the rooftop absorptivity and reflector area for three US locations. Utility factors of 375, 140, and 160 are found for Phoenix, AZ, Boise, ID, and Dayton, OH, respectively, for a reflector covering the full area between panels with a roof having a minimal absorptivity. A building in Phoenix, AZ exhibits a 15% increase in the utility factor of the PV-building system when reflectors are incorporated compared to a PV-building system without reflectors, while a building in Dayton, OH showed a 22% increase in utility factor when reflectors are included between the rows of a roof-mounted PV array.
Promoting Values-Informed Development in an Elite Dual-Career Endurance Athlete
Authors: Barnes Luke T.
Published: October 2024

This case study reports a values-based intervention with an elite dual-career athlete over an intermittent 2-year time period. The longitudinal psychological support process (i.e., intake, needs analysis, case formulation, intervention, and evaluation) is reported, and practitioner reflections are provided at the end of the case study. The intervention focused on the client-led production of personal core values and the exploration of how these could inform the athlete’s behavior change and goal attainment in sport and other life areas. Monitoring and evaluation findings suggested effective integration of values within training and competition settings, based on the observation of client behaviors and qualitative feedback from the client and their coach. The case study seeks to emphasize the importance of practitioner adaptability in developing client-led, values-based interventions that aim to facilitate holistic athlete development.
Making MAVS better
Authors: Foley John F.
Published: October 2024

Promoting palmitoylation of the adaptor protein MAVS enhances the antiviral immune response.
Population pharmacokinetic modeling of ceftriaxone in cerebrospinal fluid in children: should we be using once- or twice-daily dosing for meningitis?
Authors: Boast A. , Zhang W. , Soeorg H. , Gonis G. , Di Carlo A. , Daley A. , Curtis N. , McWhinney B. , Ungerer J. P. J. , Lei A. , Standing J. F. , Gwee A.
Published: October 2024

Guidelines for bacterial meningitis in children recommend intravenous ceftriaxone 50 mg/kg (max 2 g) twice daily (BD) or 100 mg/kg (max 4 g) once daily (OD), leaving the decision regarding the dose frequency to the prescriber. We investigated the cerebrospinal fluid (CSF) penetration of ceftriaxone to evaluate whether one dosing regimen is superior. Unbound ceftriaxone concentrations were measured in serum and CSF samples from children aged 0–18 years treated with ceftriaxone if there was a sample remaining after clinical tests were performed. A serum–CSF population pharmacokinetic model was developed using non-linear mixed-effects modeling. The once- and twice-daily dosing regimens were simulated, and the probability of target attainment (PTA) was determined for maintaining a CSF concentration above a minimum inhibitory concentration (MIC) of 1 mg/L for common meningitis pathogens and 4 mg/L for
Staphylococcus aureus
for 100% of the dosing interval. Sixteen serum and 87 CSF samples were collected from 98 children (age range 0.1–18.5 years). The final two-compartment serum–CSF model included a renal maturation function with weight scaling on clearance and volume of distribution. The estimated serum:CSF uptake was 20.1%. For MIC 1 mg/L, the 24 h PTA was higher for OD (88%) compared with BD (53%) dosing, although both achieved a 100% PTA at steady state. For
S. aureus
(MIC 4 mg/L), neither dosing regimen was sufficient. Our findings support the use of a 100 mg/kg once daily regimen for empirical treatment of bacterial meningitis due to earlier achievement of the pharmacodynamic target. Neither dosing regimen was adequate for
S. aureus
meningitis.
Complete genome sequence of
Rhodococcus qingshengii
phage Perlina
Authors: Jaryenneh James , Krishna Rohan , Schoeniger Joseph S. , Mageeney Catherine M.
Published: October 2024

Rhodococcus
phage Perlina is a novel phage isolated on
Rhodococcus qingshengii
S10. Perlina encodes 112 open reading frames with typical phage structural genes identified and 3 tRNAs (tRNA-Ile, tRNA-Met, and tRNA-Asn). Few close relatives can be identified at the nucleotide level, suggesting a new phage species.
Metagenomic, metabolomic, and lipidomic shifts associated with fecal microbiota transplantation for recurrent
Clostridioides difficile
infection
Authors: McMillan Arthur S. , Zhang Guozhi , Dougherty Michael K. , McGill Sarah K. , Gulati Ajay S. , Baker Erin S. , Theriot Casey M.
Published: October 2024

Recurrent
C. difficile
infection (rCDI) is an urgent public health threat, for which the last resort and lifesaving treatment is a fecal microbiota transplant (FMT). However, the exact mechanisms that mediate a successful FMT are not well-understood. Here, we use longitudinal stool samples collected from patients undergoing FMT to evaluate intra-individual changes in the microbiome, metabolome, and lipidome after successful FMTs relative to their baselines pre-FMT. We show changes in the abundance of many lipids, specifically a decrease in acylcarnitines post-FMT, and a shift from conjugated bile acids pre-FMT to deconjugated secondary bile acids post-FMT. These changes correlate with a decrease in Enterobacteriaceae, which encode carnitine metabolism genes, and an increase in Lachnospiraceae, which encode bile acid altering genes such as bile salt hydrolases (BSHs) and the bile acid-inducible (
bai
) operon, post-FMT. We also show changes in gut microbe-encoded amino acid biosynthesis genes, of which Enterobacteriaceae was the primary contributor to amino acids
C. difficile
is auxotrophic for. Liquid chromatography, ion mobility spectrometry, and mass spectrometry (LC-IMS-MS) revealed a shift from microbial conjugation of primary bile acids pre-FMT to secondary bile acids post-FMT. Here, we define the structural and functional changes associated with a successful FMT and generate hypotheses that require further experimental validation. This information is meant to help guide the development of new microbiota-focused therapeutics to treat rCDI.

IMPORTANCE

Recurrent
C. difficile
infection is an urgent public health threat, for which the last resort and lifesaving treatment is a fecal microbiota transplant. However, the exact mechanisms that mediate a successful FMT are not well-understood. Here, we show changes in the abundance of many lipids, specifically acylcarnitines and bile acids, in response to FMT. These changes correlate with Enterobacteriaceae pre-FMT, which encodes carnitine metabolism genes, and Lachnospiraceae post-FMT, which encodes bile salt hydrolases and
baiA
genes. There was also a shift from microbial conjugation of primary bile acids pre-FMT to secondary bile acids post-FMT. Here, we define the structural and functional changes associated with a successful FMT, which we hope will help aid in the development of new microbiota-focused therapeutics to treat rCDI.
Protein aggregation is a consequence of the dormancy-inducing membrane toxin TisB in
Escherichia coli
Authors: Leinberger Florian H. , Cassidy Liam , Edelmann Daniel , Schmid Nicole E. , Oberpaul Markus , Blumenkamp Patrick , Schmidt Sebastian , Natriashvili Ana , Ulbrich Maximilian H. , Tholey Andreas , Koch Hans-Georg , Berghoff Bork A.
Published: October 2024

Bacterial dormancy is a valuable strategy to survive stressful conditions. Toxins from chromosomal toxin-antitoxin systems have the potential to halt cell growth, induce dormancy, and eventually promote a stress-tolerant persister state. Due to their potential toxicity when overexpressed, sophisticated expression systems are needed when studying toxin genes. Here, we present a moderate expression system for toxin genes based on an artificial 5′ untranslated region. We applied the system to induce expression of the toxin gene
tisB
from the chromosomal type I toxin-antitoxin system
tisB/istR-1
in
Escherichia coli
. TisB is a small hydrophobic protein that targets the inner membrane, resulting in depolarization and ATP depletion. We analyzed TisB-producing cells by RNA-sequencing and revealed several genes with a role in recovery from TisB-induced dormancy, including the chaperone genes
ibpAB
and
spy
. The importance of chaperone genes suggested that TisB-producing cells are prone to protein aggregation, which was validated by an
in vivo
fluorescent reporter system. We moved on to show that TisB is an essential factor for protein aggregation upon DNA damage mediated by the fluoroquinolone antibiotic ciprofloxacin in
E. coli
wild-type cells. The occurrence of protein aggregates correlates with an extended dormancy duration, which underscores their importance for the life cycle of TisB-dependent persister cells.

IMPORTANCE

Protein aggregates occur in all living cells due to misfolding of proteins. In bacteria, protein aggregation is associated with cellular inactivity, which is related to dormancy and tolerance to stressful conditions, including exposure to antibiotics. In
Escherichia coli
, the membrane toxin TisB is an important factor for dormancy and antibiotic tolerance upon DNA damage mediated by the fluoroquinolone antibiotic ciprofloxacin. Here, we show that TisB provokes protein aggregation, which, in turn, promotes an extended state of cellular dormancy. Our study suggests that protein aggregation is a consequence of membrane toxins with the potential to affect the duration of dormancy and the outcome of antibiotic therapy.
Development of an infant colon simulating
in vitro
model, I-TIM-2, to study the effects of modulation strategies on the infant gut microbiome composition and function
Authors: Colberg Olivia , Hermes Gerben D. A. , Licht Tine Rask , Wichmann Anita , Baker Adam , Laursen Martin Frederik , Wellejus Anja
Published: October 2024

The early life stages are critical for the development of the gut microbiome. Variables such as antibiotics exposure, birth-mode via Cesarean section, and formula feeding are associated with disruptions in microbiome development and are related to adverse health effects later in life. Studying the effects of microbiome-modulating strategies in infants is challenged by appropriate ethical constraints. Therefore, we developed I-TIM-2, an infant
in vitro
colonic model based on the validated, computer-controlled, dynamic model of the colon, TIM-2. The system, consisting of four separate compartments, was inoculated with feces from four healthy, primarily breastfed infants, displaying distinctive microbiome profiles. For each infant’s fecal sample, a 96-h experiment was performed, with two compartments receiving an infant diet adapted medium and two compartments additionally receiving five human milk oligosaccharides (HMOs) in physiological concentrations and proportions. Bacterial composition was determined by shotgun metagenomics and qPCR. Concentrations of short-chain fatty acids (SCFAs) and HMOs were determined by LC-MS. Microbial diversity and high amounts of inoculum-derived species were preserved in the model throughout each experiment. Microbiome composition and SCFA concentrations were consistent with published data from infants. HMOs strongly modulated the microbiome composition by stimulating relative proportions of
Bifidobacterium
. This affected the metabolic output and resulted in an increased production of acetic and formic acid, characteristic of bifidobacterial HMO metabolism. In conclusion, these data demonstrate the development of a valid model to study the dynamics and modulations of the infant gut microbiome and metabolome.

IMPORTANCE

The infant gut microbiome is intricately linked to the health of its host. This is partly mediated through the bacterial production of metabolites that interact with the host cells. Human milk shapes the establishment of the infant gut microbiome as it contains human milk sugars that select for primarily bifidobacteria. The establishment can be disrupted by modern interventions such as formula feeding. This can alter the microbiome composition and metabolite production profile, which can affect the host. In this article, we set up an infant
in vitro
colonic model to study microbiome interactions and functions. In this model, we investigated the effects of human milk sugars and their promotion of bifidobacteria at the expense of other bacteria. The model is an ideal system to assess the effects of various modulating strategies on the infant gut microbiome and its interactions with its host.
Coexisting invasive ductal carcinoma arising within a benign phyllodes tumour
Authors: Salem Reem , Wu Fiona , Andaleeb Uzma , Ahmed Ibrahim
Published: October 2024

A woman in her 40s presented to the breast clinic with a 2-year history of an enlarging right breast lump. Examination revealed a 10 cm firm mass in the upper outer quadrant of the right breast. MRI and ultrasonography results revealed an 8 cm mass in the right breast and suspicious axillary nodes. Biopsy results of this mass revealed a sclerosed fibroadenoma (B2). Excision of the right breast lump had shown a benign phyllodes tumour, containing an incidental invasive ductal carcinoma and high-grade ductal carcinoma in situ. The patient underwent a right breast cavitectomy and sentinel lymph node biopsy, which revealed no further disease. She received adjuvant radiotherapy, chemotherapy and anti-HER2 treatment, and has remained disease-free at 20-month follow-up. The coexistence of an invasive carcinoma arising within a benign phyllodes tumour is rare. This case report underscores the importance of thoroughly examining excised specimens for phyllodes tumour to exclude malignant components.
Vitreoretinal lymphoma: the importance of cerebral spinal fluid evaluation at initial diagnosis
Authors: Silverman Rebecca F , Abramson David H , Canestraro Julia , Grommes Christian , Francis Jasmine H
Published: October 2024

Background/aims

To determine if patients with vitreoretinal lymphoma (VRL) and concomitant central nervous system lymphoma (CNSL) may present without brain MRI findings, but possess cerebrospinal fluid (CSF) suspicious for lymphoma.

Methods

This was a retrospective, single-centre, observational study evaluating patients with a diagnosis or suspicion of VRL seen at Memorial Sloan Kettering Cancer Center between 2006 and 2024. Patients were included if the final diagnosis was biopsy-proven CNSL and both MRI brain with and without contrast±CSF evaluation (obligatory for inclusion if MRI negative) were performed at the initial diagnostic workup. Patients were excluded if CNS disease treatment (brain, spine or CSF) preceded ocular disease. Patients with prior extra-CNS disease were included. Clinical records and radiographic imaging were retrospectively reviewed and relevant data were recorded for each patient. We evaluated the proportion of patients with MRI negative and CSF suspicious for lymphoma. Subgroup analysis included imaging features, pathology, treatment and disease course.

Results

We identified 65 patients. Of the 65 patients at the presentation of VRL, 30 had negative MRI brain and CSF, 16 had positive brain MRI and negative CSF and 8 had both positive MRI brain and CSF. 11 (16.9%) had CSF suspicious for lymphoma without positive findings on MRI of the brain. In this subgroup, the median age was 66 years (range 49–82) and 36% were female. 86% of these patients were asymptomatic neurologically. 73% underwent systemic treatment. At a mean 3 years follow-up, 91% of patients were living.

Conclusion

In patients with suspected VRL, it is possible to have CSF test positive for lymphoma in the context of negative brain MRI. This suggests, when evaluating VRL patients for concomitant CNS disease, CSF evaluation leads to earlier detection and systemic treatment, even when MRI brain findings are negative. In our cohort, an absence of CSF evaluation in the context of negative brain MRI could have missed 16.9% of patients with CNS lymphoma.
Low-volume combined aerobic and resistance high-intensity interval training in type 2 diabetes: a randomised controlled trial
Authors: Gajanand Trishan , Cox Emily R , Keating Shelley E , Brown Wendy J , Hordern Matthew D , Burton Nicola W , Chachay Veronique S , Gomersall Sjaan R , Fassett Robert G , Coombes Jeff S
Published: October 2024

Objective

The objective of this study was to compare the effects of novel, time-efficient, low-volume combined aerobic and resistance high-intensity interval training (C-HIIT), and current exercise guidelines (210 min/week of combined moderate-intensity continuous training (C-MICT)), with waitlist control (CON) on glycaemic control in people with type 2 diabetes mellitus (T2D).

Methods

Sixty-nine low-active people with T2D were randomised to 8 weeks of supervised C-HIIT (78 min/week), supervised C-MICT (210 min/week), or waitlist CON. Those in waitlist CON were re-randomised to supervised C-HIIT/C-MICT at week 8. Following 8 weeks of supervised training, participants completed 10 months of self-directed exercise. Outcomes were assessed at baseline, week 8 and month 12. Participants in waitlist CON were only included in the exercise groups for the month 12 analysis. Analyses were completed using intention-to-treat analysis of covariance (n=69; week 8) and linear mixed modelling (n=63; month 12).

Results

Compared with CON, at week 8, HbA1cdecreased in C-HIIT (adjusted mean difference: –0.7% (95% CI –1.3, –0.2%)) and C-MICT (–1.2% (–1.9, –0.6%)). There were also improvements in C-HIIT and C-MICT versus CON at week 8 for fat mass (–1.9 (–3.1, –0.6) and –1.5 (–2.6, –0.4) kg, respectively), lean mass (1.5 (0.8, 2.3) and 0.9 (0.1, 1.7) kg), and exercise capacity (124 (77, 171) and 49 (5, 93) s). At month 12, adherence was low, and most measures returned to baseline.

Conclusions

Low-volume C-HIIT (78 min/week) and C-MICT (210 min/week) improved glycaemic control, body composition and exercise capacity similarly over 8 weeks in people with T2D. However, at month 12, improvements were not maintained following self-directed exercise. Regardless, these data suggest that supervised low-volume C-HIIT is a time-efficient and effective strategy for improving outcomes in T2D.
Prevalence of physiological and perceptual markers of low energy availability in male academy football players: a study protocol for a cross-sectional study
Authors: Ashby Jamie , Mullen Thomas , Smith Philip , Rogers John P , Dobbin Nick
Published: October 2024

Low energy availability (LEA) is a core feature of the female athlete triad and relative energy deficiency in sport (REDs). LEA underpins multiple adverse health and performance outcomes in various athletic populations, including weight category, endurance and aesthetic sports. Recent reports suggest LEA is highly prevalent in female football, volleyball and netball, with little known on male team-sport athletes. Therefore, the study aims to identify the prevalence of LEA among male academy football players (16–23 years), using surrogate markers that align with the International Olympic Committee REDs Clinical Assessment Tool-Version 2. A cross-sectional study design will be used with physiological and perceptual markers of LEA measured. The study will seek to recruit 355 players to complete several online questionnaires believed to be associated with LEA, measured using a 24-hour food and activity diary. Of the 355 players, a subsample (n=110) will complete an additional 3-day food and activity diary, provide a venous blood sample to measure levels of total testosterone and free triiodothyronine, and have resting metabolic rate (RMR) measured to determine RMRratio. The prevalence of LEA will be determined using the low (<30 kcal·kgFFM-1·day-1) domain of energy availability and divided by the total number of participants. Descriptive statistics will be used to summarise the whole group and difference status of energy availability (eg, low, reduced, optimal, high). A univariable and multivariable binary logistic regression analysis will be modelled to assess the association of various surrogate markers with the presence of LEA.
EASIX-guided risk stratification for complications and outcome after CAR T-cell therapy with ide-cel in relapsed/refractory multiple myeloma
Authors: Frenking Jan H , Zhou Xiang , Wagner Vivien , Hielscher Thomas , Kauer Joseph , Mai Elias K , Friedrich Mirco J , Michel Christian S , Hajiyianni Marina , Breitkreutz Iris , Costello Patrick , Nadeem Omar , Weinhold Niels , Goldschmidt Hartmut , Schmitt Anita , Luft Thomas , Schmitt Michael , Müller-Tidow Carsten , Topp Max , Einsele Hermann , Dreger Peter , Munshi Nikhil C , Sperling Adam S , Rasche Leo , Sauer Sandra , Raab Marc S
Published: October 2024

Background

Chimeric antigen receptor (CAR) T-cell therapy has demonstrated significant benefits in the treatment of relapsed/refractory multiple myeloma (RRMM). However, these outcomes can be compromised by severe complications, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS) and immune effector cell-associated hematotoxicity (ICAHT), predisposing for life-threatening infections.

Methods

This retrospective observational study examined a total of 129 patients with RRMM who had received idecabtagene vicleucel (ide-cel) at two major myeloma centers in Germany and one center in the USA to assess the Endothelial Activation and Stress Index (EASIX) as a risk marker for an unfavorable clinical course and outcome after CAR T-cell therapy. EASIX is calculated by lactate dehydrogenase (U/L) × creatinine (mg/dL) / platelets (109cells/L) and was determined before lymphodepletion (baseline) and at the day of CAR T-cell infusion (day 0). The analysis was extended to EASIX derivatives and the CAR-HEMATOTOX score.

Results

An elevated baseline EASIX (>median) was identified as a risk marker for severe late ICAHT, manifesting with an impaired hematopoietic reconstitution and pronounced cytopenias during the late post-CAR-T period. Patients with high EASIX levels (>upper quartile) were particularly at risk, as evidenced by an increased rate of an aplastic phenotype of neutrophil recovery, severe late-onset infections and ICANS. Finally, we found associations between baseline EASIX and an inferior progression-free and overall survival. Moreover, the EASIX at day 0 also demonstrated potential to serve as a risk marker for post-CAR-T complications and adverse outcomes.

Conclusions

In conclusion, EASIX aids in risk stratification at clinically relevant time points prior to CAR T-cell therapy with ide-cel. Increased EASIX levels might help clinicians to identify vulnerable patients to adapt peri-CAR-T management at an early stage.
Geographic, ecological, and temporal patterns of seabird mortality during the 2022 HPAI H5N1 outbreak on the island of Newfoundland
Authors: McPhail Gretchen M. , Collins Sydney M. , Burt Tori V. , Careen Noah G. , Doiron Parker B. , Avery-Gomm Stephanie , Barychka Tatsiana , English Matthew D. , Giacinti Jolene A. , Jones Megan E.B. , Provencher Jennifer F. , Soos Catherine , Ward Christopher R.E. , Duffy Steven , Wilhelm Sabina I. , Wight Jordan , Rahman Ishraq , Hargan Kathryn E. , Lang Andrew S. , Montevecchi William A.
Published: October 2024

Highly pathogenic avian influenza (HPAI) H5N1 caused mass mortality of wildlife across the North Atlantic in 2022. Following European outbreaks, the first North American case was detected on the island of Newfoundland, Canada in November 2021, before spreading throughout North America. During the following summer, Newfoundland and surrounding islands (NFLD) experienced one of the most significant mortalities in Canadian provinces, with seabirds being the most affected taxa. From surveys and citizen reports, we estimate that 13 517 mortalities that can be attributed to HPAI occurred in NFLD from April to September 2022. Most estimated mortalities were among Northern Gannets ( Morus bassanus (Linnaeus, 1758)) (6596), Common Murres ( Uria aalge (Pontoppidan, 1763)) (5992), Atlantic Puffins ( Fratercula arctica (Linnaeus, 1758)) (282), and Black-legged Kittiwakes ( Rissa tridactyla (Linnaeus, 1758)) (217). Mortality reports moved from west to east along the southern, then eastern NFLD coast, and peaked in July and August. We formulated exploratory hypotheses regarding traits that could contribute to infection and mortality. Species differences in mortality most strongly associated with inter-nest distance, breeding phenology, and at-sea overlap with allospecifics from other colonies. Unprecedented seabird mortality and ongoing transmission within the circulating avian influenza viruses highlight the need for continued monitoring and development of conservation strategies.
Prospects for detecting the couplings of axion-like particle with neutrinos at the CEPC
Authors: Yue Chong-Xing , Li Xin-Yang , Sun Xiao-Chen
Published: October 2024

We explore the possibility of detecting the couplings of axion-like particle (ALP) with leptons from their loop-level impact on the ALP couplings to electroweak (EW) gauge bosons via the signal process "Equation missing" at the circular electron positron collider (CEPC) and obtain prospective sensitivities to the ALP-lepton couplings. Our numerical results show that the CEPC with the center of mass energy $$\sqrt{s}=240~(91)$$

s

=
240

(
91
)

GeV and the integrated luminosity $$\mathcal {L}=5.6~(16)$$

L
=
5.6

(
16
)

$$\hbox {ab}^{-1}$$

ab

-
1

might be sensitive for probing the ALP-lepton couplings in the ALP mass range from 10 GeV to 130 (50) GeV, where the prospective sensitivities to the ALP-neutrino coupling $$Tr(g_{a\nu \nu })/f_a$$

T
r

(

g

a
ν
ν

)

/

f
a

can be as low as 0.016 (0.012) $$\hbox {GeV}^{-1}$$

GeV

-
1

and $$0.0031~(2.8 \times 10^{-4})$$

0.0031

(
2.8
×

10

-
4

)

$$\hbox {GeV}^{-1}$$

GeV

-
1

for $$c_{R}=0$$

c
R

=
0

and $$c_{R}=c_{L}$$

c
R

=

c
L

, and to the ALP-charged lepton coupling $$Tr(g_{a\ell \ell })/f_a$$

T
r

(

g

a
ℓ
ℓ

)

/

f
a

can be as low as 0.035 (0.07) $$\hbox {GeV}^{-1}$$

GeV

-
1

for $$c_{L}=0$$

c
L

=
0

. We find that the prospective sensitivities given by the CEPC are not covered by the current and expected exclusion regions in some ALP mass intervals. The CEPC has the potential for exploring the ALP-neutrino couplings via some promising processes induced by the ALP-EW gauge boson couplings in the future.
$$\phi $$ meson mass and decay width in magnetized strange hadronic matter
Authors: Chahal Nisha , Kumar Rajesh , Dutt Suneel , Kumar Arvind
Published: October 2024

We investigate the medium modifications in mass and decay width of $$\phi $$
ϕ
meson in the presence of an external magnetic field. The in-medium mass of $$\phi $$
ϕ
meson has been calculated using the decay process $$\phi $$
ϕ
$$\rightarrow $$
→
$$K {\bar{K}}$$

K

K

¯

at one-loop level. The medium modifications are introduced by using a chiral SU(3) model employing a mean-field effective approach. Due to the introduction of the magnetic field, masses of charged $$K^+$$

K
+

and $$K^-$$

K
-

increases with advancing magnetic field values. A negligible change in the value of neutral $$K^0$$

K
0

and $${\bar{K}}^0$$

K

¯

0

has been observed for varying magnetic fields. Due to electromagnetic interactions with charged K and $${\bar{K}}$$

K

¯

mesons, there is a gradual augmentation in the effective mass of $$\phi $$
ϕ
meson. The probability of the mentioned decay process ceases to be zero for low density and strangeness fraction values at higher magnetic field values. Investigating the decay width and effective mass of $$\phi $$
ϕ
meson under the influence of an external magnetic field is relevant to understanding the hadronic matter properties under extreme conditions achievable at heavy-ion collision experiments.
Statistical Testing of Quantum Programs via Fixed-Point Amplitude Amplification
Authors: Kang Chan Gu , Lee Joonghoon , Oh Hakjoo
Published: October 2024

We present a new technique for accelerating quantum program testing. Given a quantum circuit with an input/output specification, our goal is to check whether executing the program on the input state produces the expected output. In quantum computing, however, it is impossible to directly check the equivalence of the two quantum states. Instead, we rely on statistical testing, which involves repeated program executions, state measurements, and subsequent comparisons with the specified output. To guarantee a high level of assurance, however, this method requires an extensive number of measurements. In this paper, we propose a solution to alleviate this challenge by adapting Fixed-Point Amplitude Amplification (FPAA) for quantum program testing. We formally present our technique, demonstrate its ability to reduce the required number of measurements as well as runtime cost without sacrificing the original statistical guarantee, and showcase its runtime effectiveness through case studies.
Full Iso-Recursive Types
Authors: Zhou Litao , Wan Qianyong , Oliveira Bruno C. d. S.
Published: October 2024

There are two well-known formulations of recursive types: iso-recursive and equi-recursive types. Abadi and Fiore [LICS 1996] have shown that iso- and equi-recursive types have the same expressive power. However, their encoding of equi-recursive types in terms of iso-recursive types requires explicit coercions. These coercions come with significant additional computational overhead, and complicate reasoning about the equivalence of the two formulations of recursive types. This paper proposes a generalization of iso-recursive types called full iso-recursive types. Full iso-recursive types allow encoding all programs with equi-recursive types without computational overhead. Instead of explicit term coercions, all type transformations are captured by computationally irrelevant casts, which can be erased at runtime without affecting the semantics of the program. Consequently, reasoning about the equivalence between the two approaches can be greatly simplified. We present a calculus called λ

Fi

µ
, which extends the simply typed lambda calculus (STLC) with full iso-recursive types. The λ

Fi

µ
calculus is proved to be type sound, and shown to have the same expressive power as a calculus with equi-recursive types. We also extend our results to subtyping, and show that equi-recursive subtyping can be expressed in terms of iso-recursive subtyping with cast operators.
Non-termination Proving at Scale
Authors: Raad Azalea , Vanegue Julien , O’Hearn Peter
Published: October 2024

Program termination is a classic non-safety property whose falsification cannot in general be witnessed by a finite trace. This makes testing for non-termination challenging, and also a natural target for symbolic proof. Several works in the literature apply non-termination proving to small, self-contained benchmarks, but it has not been developed for large, real-world projects; as such, despite its allure, non-termination proving has had limited practical impact. We develop a
compositional
theory for non-termination proving, paving the way for its
scalable
application to large codebases. Discovering non-termination is an under-approximate problem, and we present UNTer, a
sound and complete
under-approximate logic for proving non-termination. We then extend UNTer with separation logic and develop UNTer
SL
for heap-manipulating programs, yielding a compositional proof method amenable to automation via under-approximation and bi-abduction. We extend the Pulse analyser from Meta and develop Pulse
∞
, an automated, compositional prover for non-termination based on UNTer
SL
. We have run Pulse
∞
on large codebases and libraries, each comprising hundreds of thousands of lines of code, including OpenSSL, libxml2, libxpm and CryptoPP; it discovered several previously-unknown non-termination bugs and have reported them to developers of these libraries.
Synthesizing Formal Semantics from Executable Interpreters
Authors: Liu Jiangyi , Murphy Charlie , Grover Anvay , Johnson Keith J.C. , Reps Thomas , D’Antoni Loris
Published: October 2024

Program verification and synthesis frameworks that allow one to customize the language in which one is interested typically require the user to provide a formally defined semantics for the language.

Because writing a formal semantics can be a daunting and error-prone task, this requirement stands in the way of such frameworks being adopted by non-expert users.

We present an algorithm that can automatically synthesize inductively defined syntax-directed semantics when given (i) a grammar describing the syntax of a language and (ii) an executable (closed-box) interpreter for computing the semantics of programs in the language of the grammar.

Our algorithm synthesizes the semantics in the form of Constrained-Horn Clauses (CHCs), a natural, extensible, and formal logical framework for specifying inductively defined relations that has recently received widespread adoption in program verification and synthesis.

The key innovation of our synthesis algorithm is a Counterexample-Guided Synthesis (CEGIS) approach that breaks the hard problem of synthesizing a set of constrained Horn clauses into small, tractable expression-synthesis problems that can be dispatched to existing SyGuS synthesizers.

Our tool Synantic synthesized inductively-defined formal semantics from 14 interpreters for languages used in program-synthesis applications.

When synthesizing formal semantics for one of our benchmarks, Synantic unveiled an inconsistency in the semantics computed by the interpreter for a language of regular expressions; fixing the inconsistency resulted in a more efficient semantics and, for some cases, in a 1.2x speedup for a synthesizer solving synthesis problems over such a language.
A Modal Type Theory of Expected Cost in Higher-Order Probabilistic Programs
Authors: Rajani Vineet , Barthe Gilles , Garg Deepak
Published: October 2024

The design of online learning algorithms typically aims to optimise the incurred loss or
cost
, e.g., the number of classification mistakes made by the algorithm. The goal of this paper is to build a type-theoretic framework to
prove
that a certain algorithm achieves its stated bound on the cost. Online learning algorithms often rely on randomness, their loss functions are often defined as expectations, precise bounds are often non-polynomial (e.g., logarithmic) and proofs of optimality often rely on potential-based arguments. Accordingly, we present pλ-amor, a type-theoretic graded modal framework for analysing (expected) costs of higher-order
probabilistic
programs with recursion. pλ-amor is an effect-based framework which uses graded modal types to represent potentials, cost and probability at the type level. It extends prior work (λ-amor) on cost analysis for
deterministic
programs. We prove pλ-amor sound relative to a Kripke step-indexed model which relates potentials with probabilistic coupling. We use pλ-amor to prove cost bounds of several examples from the online machine learning literature. Finally, we describe an extension of pλ-amor with a graded comonad and describe the relationship between the different modalities.