bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of different modes of administration of esketamine combined with supraclavicular brachial plexus block on the incidence of rebound pain after upper limb fracture surgery: study protocol for a single-centre, double-blinded, randomised controlled trial
Authors: Jiang Wencai , Peng Yanhua , Chen Xuemeng , Fu Lijuan , Zhai Wenhu , Zhang Xianjie , Zhou Yukai
Published: December 2024

Background

Supraclavicular brachial plexus block (SCB) is a common regional analgesic technique for upper limb fracture surgery, but it often leads to rebound pain. Our primary aim is to determine whether different administration methods of esketamine can reduce rebound pain in patients undergoing SCB for upper limb fracture surgery.

Methods/design

This study is designed as a single-centre, double-blinded, prospective, randomised controlled trial. Patients undergoing upper limb fracture surgery, who plan to use a tourniquet, aged 18–60 years, with a body mass index of 18–30 kg/m2and an American Society of Anaesthesiologists classification of I–III will be randomised into three groups after providing written informed consent: group N (perineural esketamine/ropivacaine); group V (intravenous esketamine/perineural ropivacaine); and group C (perineural ropivacaine). The primary outcome will be the percentage of patients experiencing rebound pain within 24 hours postoperatively. Secondary outcomes include the Numeric Rating Scale (NRS) score of rebound pain, the onset of rebound pain, (since performing SCB), the cumulative area under the curve of NRS pain severity scores through 48 hours postsurgery, postoperative opioid consumption at 48 hours postoperatively, onset and duration of the sensory blockade, onset and duration of the motor blockade and adverse reactions and adverse events. Patients will be followed-up to 48 hours postoperatively.

Discussions

This protocol describes the design of a randomised controlled trial to evaluate the effect of different modes of administration of esketamine combined with SCB on the incidence of rebound pain after upper limb fracture surgery. The results may help to identify the most effective methods for managing pain in patients undergoing upper limb fracture surgery.

Ethics and dissemination

This study has been approved by the Ethics Committee of the Deyang People’s Hospital (2023-03-010-K01). It was registered on the Chinese Clinical Trials Registry on 24 August 2023. We intend to publish the results in a peer-reviewed journal.

Trial registration number

ChiCTR2300075083.
‘You grow with the allergy’: a grounded theory study of families’ experiences with food allergy risk or diagnosis in early childhood
Authors: Hörold Madlen , Gerhardinger Katharina , König Mara , Rohr Magdalena , Weigt Julia , Apfelbacher Christian , Brandstetter Susanne
Published: December 2024

Objective

Childhood food allergy is increasing in western societies. Preventing and managing food allergies is therefore essential for both parents and children. Given the limited previous research on parents’ experiences of food allergy prevention in early childhood, this study aimed to develop a grounded theory to understand the experiences and interactions of families whose children are at risk of, or have been diagnosed with, food allergy.

Design

Using a constructivist grounded theory approach, we used initial, focused and theoretical coding, as well as constant comparative analysis and memoing to interpret our data.

Setting

Thematic interviews were conducted in Germany between March and September 2022.

Participant

We included 28 carers (25 mothers and 3 fathers) of children aged 0–3 years diagnosed with food allergy or at risk of food allergy. We recruited participants using snowball and theoretical sampling.

Results

We developed a theory that we named ‘negotiating uncertainty in childhood food allergy’. This theory describes the experiences and interactions of families with a child at risk or diagnosed with food allergy with the central phenomena of negotiation uncertainty. Negotiation is used to transform perceived challenges of uncertainty into feelings of competence in relation to (the prevention of) food allergy. Core themes included ‘parental roles’, ‘healthcare’, ‘childcare’, ‘informal support’ and ‘family routines’. To cope with the challenges, parents relied on two main resources: self-efficacy and health literacy.

Conclusion

The study highlights the dynamic process of negotiation within families at risk of or coping with paediatric food allergy. Furthermore, our findings highlight the need to promote parental health literacy.
Schizophrenia in children, adults and older people with intellectual disability compared with the general population: a Swedish register study (IDcare)
Authors: Bakken Trine Lise , Sandberg Magnus , Axmon Anna
Published: December 2024

Background

The knowledge about the prevalence of schizophrenia among people with intellectual disabilities (ID) is sparse, particularly concerning the distribution in different age groups.

Aims

To investigate the prevalence of diagnoses in the schizophrenia spectrum among people with ID compared with the general population (gPop).

Methods

This was an 8-year longitudinal register study. The participants were all residents of Skåne on 1 January 2014. People with a diagnosis of ID (F7 in International Statistical Classification of Diseases and Related Health Problems 10th Revision) or Down syndrome (DS; Q90), or service and support for people with ID/autism spectrum disorder (ASD) comprised the ID cohort (n=14 716). After excluding family members of people in the ID cohort, the remaining population of Skåne comprised the gPop cohort (n=1 226 955).

The primary outcome measure was having at least one diagnosis in the schizophrenia spectrum (F20-F29). Secondary outcomes were single diagnoses within the schizophrenia spectrum.

Results

The prevalence of schizophrenia spectrum diagnoses was 7.2% in the ID cohort. This was more than an eightfold increase compared with the gPop (relative risk (RR) 8.45; 95% CI 7.94 to 9.00). The risk was also high among children (aged 0–18 years at the start of the study period; RR 9.42; 95% CI 7.36 to 12.05). In the subcohort comprising those with a diagnosis of DS, the risk of schizophrenia diagnosis was more than twice as high as in gPop. Concomitant ASD or genetic syndrome did not carry an excess risk among people with ID when compared with the gPop.

Conclusions

The findings of the present study support earlier assumptions that people with vulnerable brains develop psychotic disorders more frequently and that the onset age is lower than among people in the gPop. Habilitation services for children and adolescents, as well as general mental health services, should keep in mind that schizophrenia may be present when children and adolescents show severely decreased functioning, anxiety or aggressive behaviour.
Antiviral therapy for chronic hepatitis delta: new insights from clinical trials and real-life studies
Authors: Lampertico Pietro , Anolli Maria Paola , Roulot Dominique , Wedemeyer Heiner
Published: December 2024

Chronic hepatitis D (CHD) is the most severe form of viral hepatitis, carrying a greater risk of developing cirrhosis and its complications. For decades, pegylated interferon alpha (PegIFN-α) has represented the only therapeutic option, with limited virological response rates and poor tolerability. In 2020, the European Medicines Agency approved bulevirtide (BLV) at 2 mg/day, an entry inhibitor of hepatitis B virus (HBV)/hepatitis delta virus (HDV), which proved to be safe and effective as a monotherapy for up to 144 weeks in clinical trials and real-life studies, including patients with cirrhosis. Long-term BLV monotherapy may reduce decompensating events in patients with cirrhosis. The combination of BLV 2 mg with PegIFN-α increased the HDV RNA undetectability rates on-therapy but not off-therapy, compared with PegIFN monotherapy. However, combination therapy, but not BLV monotherapy, may induce hepatitis B surface antigen (HBsAg) loss in some patients. The PegIFN lambda study has been discontinued due to liver toxicity issues, while lonafarnib boosted with ritonavir showed limited off-therapy efficacy in a phase 3 study. Nucleic acid polymer-based therapy is promising but large studies are still lacking. New controlled trial data come from molecules, such as monoclonal antibodies and/or small interfering RNA, that target HBsAg or HBV RNAs, which demonstrated not only profound HDV suppression, but also HBsAg decline.

While waiting for new compounds to be approved as monotherapy or in combination, BLV monotherapy 2 mg/day remains the only approved therapy for CHD, at least in the European Union region.
Hepatic TM6SF2 activates antitumour immunity to suppress metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma and boosts immunotherapy
Authors: Zhang Yating , Xie Mingxu , Wen Jun , Liang Cong , Song Qian , Liu Weixin , Liu Yali , Song Yang , Lau Harry Cheuk Hay , Cheung Alvin Ho-Kwan , Man Kwan , Yu Jun , Zhang Xiang
Published: December 2024

Background

Transmembrane 6 superfamily member 2 (TM6SF2) has a protective role against metabolic dysfunction-associated steatotic liver disease (MASLD).

Objective

We aim to investigate the mechanistic role and therapeutic potential of hepatic TM6SF2 in MASLD-related hepatocellular carcinoma (HCC).

Design

Hepatocyte-specificTm6sf2knockout (Tm6sf2∆hep) mice were fed with high-fat/high-cholesterol (HFHC) diet or diethylnitrosamine plus HFHC diet to induce MASLD-HCC. TM6SF2 function was also evaluated in orthotopic MASLD-HCC mice. Human MASLD-HCC specimens were included to evaluate clinical significance.

Results

TM6SF2 was downregulated in tumours compared with adjacent normal tissues from MASLD-HCC patients. Hepatocyte-specificTm6sf2knockout exacerbated tumour formation in mice with diet-induced or diet-induced and carcinogen-induced MASLD-HCC. The tumour-promoting effect ofTm6sf2knockout was verified in orthotopic MASLD-HCC mice, while mice bearingTm6sf2-overexpressing tumours had opposite phenotypes. We observed the reduction of interferon-gamma (IFN-γ)+CD8+T cells in the tumours ofTm6sf2∆hepmice and orthotopicTm6sf2knockout mice, while the tumour-suppressive effect ofTm6sf2was abolished after depleting CD8+T cells. The correlation between TM6SF2 and CD8+T cells was confirmed in human MASLD-HCC tissues, inferring that TM6SF2 could promote antitumour immunity. Mechanistically, TM6SF2 directly bound to IKKβ and inhibited NF-κB signalling pathway to reduce interleukin (IL)-6 secretion, thereby activating cytotoxic CD8+T cells. IL-6 neutralisation abolished the tumour-promoting and immunosuppressive effects ofTm6sf2knockout in mice. Moreover, introducingTm6sf2by adenovirus improved immunotherapy response against MASLD-HCC in mice.

Conclusion

Hepatic TM6SF2 protects against MASLD-HCC and activates cytotoxic CD8+T cells via NF-κB-IL-6 axis. TM6SF2 is a promising strategy for sensitising MASLD-HCC to immunotherapy.
Early tumour necrosis factor antagonist treatment prevents perianal fistula development in children with Crohn’s disease: post hoc analysis of the RISK study
Authors: Adler Jeremy , Gadepalli Samir , Rahman Moshiur , Kim Sandra
Published: December 2024

Background

One in three children with Crohn’s disease develop perianal fistula complications (PFCs), among the most disturbing and difficult-to-treat disease-related complications. Retrospective evidence suggests PFCs may be preventable.

Objective

We aimed to determine if early antitumour necrosis factor-alpha (anti-TNF⍺) therapy prevents PFC development in a well-characterised prospective cohort of paediatric patients with Crohn’s disease who were free from PFC at enrolment.

Design

RISK was a multicentre inception cohort of children newly diagnosed with Crohn’s disease. We included all patients who had never experienced PFCs 30 days after study enrolment. We conducted nearest-neighbour propensity score-matched triad analyses. Matching was performed to balance patient characteristics across three mutually exclusive treatment groups based on therapy prior to either PFC development or the end of the observation period.

Results

Among 873 patients without perianal fistula, 447 matched patients were included (149 per treatment group). The presence of non-penetrating perianal lesions (large skin tags, ulcers and/or fissures) was significantly associated with PFC development, with 4-fold greater odds of PFC (OR 4.08, 95% CI (95% CI) 1.70 to 9.78; p=0.0016). Early anti-TNF⍺ therapy was associated with an 82% decrease in the odds of PFC (OR 0.18, 95% CI 0.05 to 0.66; p=0.01). Among those with perianal lesions, anti-TNF⍺ therapy was associated with 94% reduced odds of PFC development (OR 0.055, 95% CI 0.006 to 0.50; p=0.010). No other treatment group was associated with reduced risk of PFC.

Conclusion

Early anti-TNF therapy prevents perianal fistula development, especially among patients at increased risk.
Clinicopathological characteristics of light chain proximal tubulopathy: a multicentre case series
Authors: Lin Yao , Xing Guolan , Hu Ruimin , Liu Shaojun , Li Guisen , Zhang Ping , Xu Feng , Liang Dandan , Zhu Xiaodong , Zhang Mingchao , Yang Fan , Yao Xinchen , Liu Feng , Wang Yujie , Dong Shihui , Liang Shaoshan , Zeng Caihong
Published: December 2024

Aims

Light chain proximal tubulopathy (LCPT) is a rare complication of paraprotein-related diseases. We report a case series to present the clinicopathological characteristics and outcomes of LCPT.

Methods

A multicentre retrospective case series of 47 patients with LCPT, consisting of 36 crystalline, three non-crystalline, and eight mixed LCPTs, was studied between January 2007 and December 2023.

Results

The median age at diagnosis was 57 years. Presentations included proteinuria (100%), renal insufficiency (62%) and Fanconi syndrome (68%). The underlying haematological diagnoses were monoclonal gammopathy of renal significance in 81% and multiple myeloma in 19%. Monoclonal light chain (LC) was detected in all cases using serum/urine-free LC assays or immunofixation electrophoresis. Among 36 crystalline LCPTs, 34 were κ-restricted and 2 λ-restricted. Three non-crystalline LCPTs were all λ-restricted. In mixed LCPTs, seven were κ-restricted and one was λ-restricted. Notably, 66% frozen-section immunofluorescence failed to reveal restricted LC, requiring paraffin-immunofluorescence or immunoelectron microscopy. The appearance of inclusions displayed intraindividual homogeneity but interindividual heterogeneity in 42 patients and notable intraindividual heterogeneity in the remaining 5 patients. Haematological complete response, very good partial response and partial response occurred in 61%. Kidney function improved or remained stable in 84%, worsened in 8% and progressed to end-stage renal disease in 8%.

Conclusions

Proteinuria and kidney dysfunction are the most common but less-specific renal manifestations of LCPTs, with most featuring Fanconi syndrome. Crystalline LCPT, primarily associated with κ-LC, is the predominant form. Most inclusions displayed intraindividual homogeneity and interindividual heterogeneity by electron microscopy. Most achieved haematological responses and favourable renal outcomes.
Local cell therapy using CCL19-expressing allogeneic mesenchymal stem cells exerts robust antitumor effects by accumulating CD103+IL-12-producing dendritic cells and priming CD8+T cells without involving draining lymph nodes
Authors: Iida Yuichi , Harada Mamoru
Published: December 2024

Background

Immune checkpoint blockade is a promising anticancer therapy, whereas the presence of T cells in tumor sites is indispensable for its therapeutic efficacy. To promote the infiltration of T cells and dendritic cells (DCs) into the tumor, we previously proposed a local cell therapy using chemokine (C-C motif) ligand 19 (CCL19)-expressing immortalized syngeneic immortalized mesenchymal stem cells (syn-iMSC/CCL19). However, the preparation of syngeneic/autologous MSC from individual hosts limits the clinical application of this cell therapy.

Methods

In this study, we further developed a new cell therapy using allogeneic iMSC/CCL19 (allo-iMSC/CCL19) using several tumor mice models.

Results

The allo-iMSC/CCL19 therapy exerted drastic antitumor effects, in which the host’s T cells were induced to respond to allogeneic MSC. In addition, the allo-iMSC/CCL19 therapy promoted the infiltration of CD103+interleukin (IL)-12-producing DCs and priming of CD8+T cells at tumor sites compared with that using syn-iMSC/CCL19. The antitumor effect of allo-iMSC/CCL19 therapy was not influenced by fingolimod, a sphingosine 1-phosphate receptor modulator, implying no involvement of draining lymph nodes in the priming of tumor-specific T cells.

Conclusion

These results suggest that allo-iMSC/CCL19 therapy exerts dramatic antitumor effects by promoting the infiltration of CD103+IL-12-producing DCs and thereby priming tumor-specific CD8+T cells at tumor sites. This local cell therapy could be a promising approach to anticancer therapy, particularly for overcoming dysfunction in the cancer-immunity cycle.
Telomere length, in vivo Alzheimer’s disease pathologies and cognitive decline in older adults
Authors: Jung Joon Hyung , Byun Min Soo , Yi Dahyun , Ahn Hyejin , Lee Jun Ho , Lee Jang-Seok , Lee Hyun-Seob , Lee Jun-Young , Kim Yu Kyeong , Lee Yun-Sang , Kang Koung Mi , Sohn Chul-Ho , Lee Dong Young
Published: December 2024

Background

Whether telomere length (TL), an indicator of biological ageing, reflects Alzheimer’s disease (AD)-related neuropathological change remains unclear. We investigated the relationships between TL, in vivo AD pathologies, including cerebral beta-amyloid and tau deposition, and cognitive outcomes in older adults.

Methods

A total of 458 older adults were included, encompassing both cognitively normal (CN) individuals and those cognitively impaired (CI), with the CI group consisting of individuals with mild cognitive impairment or AD dementia. All participants underwent clinical and neuropsychological assessments, amyloid positron emission tomography (PET) scan and DNA extraction for measuring TL at baseline. A subset of participants (n=140) underwent tau PET scan. At follow-up, the participants underwent neuropsychological assessments annually for up to 4 years.

Results

Overall, longer TL was associated with greater brain tau deposition (B=0.139, 95% CI 0.040, 0.238) and a faster decline in global cognition (B = − 0.371, 95% CI − 0.720, –0.023). In the subgroup analysis, the association between longer TL and greater in vivo AD pathologies, as well as faster cognitive decline, was observed particularly in the CI group. Mediation analysis suggested that longer TL was associated with cognitive decline through increased tau deposition in the CI group.

Conclusion

Our finding suggests that older adults with relatively longer TL, particularly in the CI group, may have greater in vivo AD pathologies and experience more rapid cognitive decline, potentially mediated by brain tau deposition. Further studies are necessary to elucidate the biological links underlying these associations.
Incidence and prevalence of functional neurological disorder: a systematic review
Authors: Finkelstein Sara A , Diamond Clare , Carson Alan , Stone Jon
Published: December 2024

Background

Robust epidemiological data regarding population incidence and prevalence of functional neurological disorder (FND) would be helpful with regards to resource allocation and planning for this disorder, particularly given high symptom burden and high healthcare utilisation. We therefore aimed to systematically review and synthesise available data on FND incidence and prevalence.

Methods

PubMed was searched to identify original research articles that reported on the incidence or prevalence of FND. Risk of bias assessment for each study was conducted. Incidence and prevalence rates of FND were additionally estimated by extrapolating data from low risk of bias studies on functional seizures alone.

Results

Thirty-nine articles were included. Nineteen reported on FND incidence, 21 reported on prevalence. Comparison between studies was difficult due to methodological differences and significant heterogeneity of incidence and prevalence estimates was found. The incidence of FND was estimated at 10–22/100 000, while minimum prevalence of FND was estimated at 80–140/100 000, with a possible range of 50–1600/100 000. Incidence of paediatric FND was estimated to be between 1 and 18/100 000.

Conclusions

The range of incidence and prevalence varies widely across studies, with significant heterogeneity among studies and most studies likely provide underestimates due to methodological challenges. However, using our best method as a conservative estimate, there are likely a minimum of 50–100 000 people with FND in the UK, as an example country. Given that FND appears to be more prevalent than many other well-known and well-funded neurological disorders, incidence and prevalence data suggested here indicate the need for greater research and clinical funding allocation to FND programmes.
Real time continuous monitoring of injection pressure at the needle tip is better than ultrasound in early detecting intraneural injection
Authors: Dossi Roberto , Quadri Christian , Capdevila Xavier , Saporito Andrea
Published: December 2024

Introduction

During peripheral nerve blocks, inadvertent intraneural injection is not infrequent. Recently, with sonographic nerve swelling, it has been shown that intraneural injection can be detected as early as 0.4 mL. A new method based on injection pressure monitoring at the needle tip, the real pressure in the tissues, is compared with sonographic performance in early detection of intraneural injection.

Methods

This cadaver study was conducted on the upper limb of fresh cadavers. Senior anesthesiologists performed ultrasound guided intraneural injections of the nerves using a modified Visioplex needle with a fiberoptic sensor embedded. 12 injections were performed, two on each nerve (radial, ulnar, and median) for each anatomical preparation. 3 mL of saline methylene blue mix was injected at 10 mL/min. Recordings of ultrasound screen and pressure curves were blindly analyzed to evaluate nerve swelling and injection pressures.

Results

An immediate increase in injection pressure from time zero was observed in all 12 intraneural injections, with similar trends. After only 0.2 mL, intraneural injection was clearly identified as the pressure curves had already risen to an average of 120 mm Hg (SD 5). Nerve swelling was observed in 10 of 12 injections (83%). This was evident after an average of 1.2 mL (SD 0.5). Following injections, dissection of specimens confirmed intraneural spread in all cases.

Conclusion

Pressure monitoring at the needle tip consistently showed a pressure rise from the onset of injection and proved to be a more sensitive and earlier indicator of intraneural injection than sonographic nerve swelling.
Geodynamic evolution of felsic magmatism in the Yellowknife greenstone belt, N.W.T., Canada: evidence for Archean magmatism in a volatile-saturated environment
Authors: Speight Sarah C. , McFarlane Christopher R.M. , Hanley Jacob J.
Published: December 2024

The Yellowknife greenstone belt in the Archean Slave province, N.W.T., Canada, hosts multiple generations of porphyry dikes and plutons, including feldspar–quartz porphyry (FQP), quartz porphyry (QZP), and aplitic dikes, along with the regional Ryan Lake Pluton (RLP), Defeat Suite, and Duckfish granites. Chondrite-normalized REE patterns differentiate three aplite groups and their genetically related parental plutons. The RLP and aplite-1(a) dikes have smooth REE profiles that decrease from LREE to HREE, shared by FQP and QZP dikes. The Defeat Suite granite and aplite-1(b) dikes display flatter REE patterns with a strong negative Eu anomaly. Duckfish granite and aplite-2 dikes share concave-up REE patterns with weak positive Ce (up to Ce/Ce* = 3.1) and strong negative Eu anomalies. These geochemical distinctions link subvolcanic intrusions with source plutons. Aplite dikes were further characterized by petrogenetic models, establishing four stages of dike emplacement during pluton crystallization. Progressive stages of emplacement show increasing differentiation (e.g., decreasing Al2O3, MgO, TiO2, Eu/Eu*). Evidence of volatile saturation was observed macroscopically as cm-scale quartz cores and quartz pods. Further study of volatile evolution and its relationship to mineralization (e.g., timing, volatile composition) is warranted.
Evaluation of pheromone- and floral-baited traps for monitoring western corn rootworm (Coleoptera: Chrysomelidae) beetles in Canada
Authors: van Herk Willem G. , Bailey Terisha , Saguez Julien , Smith Jocelyn L. , Farhan Yasmine
Published: December 2024

Western corn rootworm (WCR), Diabrotica virgifera virgifera, was first detected in British Columbia (BC) in 2016, resulting in the need for a trapping method that can detect beetles at low population levels and that can potentially mass trap beetles in sweet corn processing and distribution outlets. Based on early field experiments run in BC in 2019 and 2020, four trap types, baited with sex pheromone or floral lures, were evaluated in BC, Ontario, and Quebec for two 2-week periods during the swarming period in 2021. Trap captures were scored 0–10 based on relative captures, with the method with greatest captures scored as 10. Captures of male beetles were greatest on pheromone-baited PAL (“cloak”) (mean score of all 2021 experiments = 9.6) and PALs traps (8.6), and significantly lower with pheromone-baited Delta (3.4) and KLP (“hat”) (1.5), or floral-baited PAL (2.1) and PALs traps (1.9). Captures of female beetles were greatest on floral-baited PALs (8.7), PAL (8.4), and Delta traps (5.0), and low on KLP (1.5) and all other trapping methods (<1). In follow-up experiments run in 2023, pheromone-baited PAL traps captured >180× more beetles than non-baited Pherocon AM traps. Together these results indicate that PAL, PALs, and Delta traps can be used for the early detection of male and female WCR when baited with pheromone and floral lures, respectively, in Canada, both to determine the onset of the beetle swarming season for timing of foliar insecticide applications, and to monitor the spread of WCR to new areas.
Numerical and analytical modelling of wellbore storage effects in low-enthalpy geothermal well tests
Authors: Bruijnen P. M.
Published: December 2024

In geothermal wells, build-up phases of well tests are typically executed with a surface shut-in, rather than with a downhole shut-in. Therefore, wellbore physics may play a dominant, but undesirable, role in the system's pressure response as recorded by the downhole pressure gauge. Numerical simulations were carried out to investigate to what extent these effects complicate the analysis of the well test and the deduction of the reservoir characteristics. Numerical models, supported by analytical modelling of well tests of field cases, show that significant portions of the Bourdet derivatives of geothermal well tests are expressions of physical effects in the wellbore, rather than the reservoir's pressure response. These wellbore storage effects in low-enthalpy geothermal wells are more intense than commonly reported in the literature. In addition, they may last for a very long time and vary continuously during the build-up. They cannot be represented accurately with the known analytical solutions commonly available in analytical well-test software. In many cases the early, middle and late time regions of the reservoir response on the derivative plot have only developed partially, or might be completely missing. Due to their intensity and duration, the wellbore storage effects can obliterate the true reservoir response, thereby making a reliable analysis of the reservoir characteristics impossible. This will undoubtedly lead to incorrect interpretations of the skin or reservoir properties. It is therefore strongly recommended that well tests in geothermal wells are executed using a downhole shut-in device, such that the unwanted wellbore physics are fully eliminated and the downhole pressure gauges only measure the true reservoir response.
The Tale of Errors in Microservices
Authors: Lee I-Ting Angelina , Zhang Zhizhou , Parwal Abhishek , Chabbi Milind
Published: December 2024

Microservice architecture is the computing paradigm of choice for large, service-oriented software catering to real-time requests. Individual programs in such a system perform Remote Procedure Calls (RPCs) to other microservices to accomplish sub-tasks. Microservices are designed to be robust; top-level requests can succeed despite errors returned from RPC sub-tasks, referred to as

non-fatal errors
.

Because of this design, the top-level microservices tend to ''live with'' non-fatal errors. Hence, a natural question to ask is ''how prevalent are non-fatal errors and what impact do they have on the exposed latency of top-level requests?''

In this paper, we present a large-scale study of errors in microservices. We answer the aforementioned question by analyzing 11 Billion RPCs covering 1,900 user-facing endpoints at the Uber serving requests of hundreds of millions of active users. To assess the latency impact of non-fatal errors, we develop a methodology that projects potential latency savings for a given request as if the time spent on failing APIs were eliminated. This estimator allows ranking and bubbling up those APIs that are worthy of further investigations, where the non-fatal errors likely resulted in operational inefficiencies. Finally, we employ our error detection and impact estimation techniques to pinpoint operational inefficiencies, which a) result in a tail latency reduction of a critical endpoint by 30% and b) offer insights into common inefficiency-introducing patterns.
Computational Complexity of
k
-stable Matchings
Authors: Aziz Haris , Csáji Gergely , Cseh Ágnes
Published: December 2024

We study deviations by a group of agents in the three main types of matching markets: the house allocation, the marriage, and the roommates models. For a given instance, we call a matching
k-stable
if no other matching exists that is more beneficial to at least
k
out of the
n
agents. The concept generalizes the recently studied majority stability [
57
]. We prove that whereas the verification of
k
-stability for a given matching is polynomial-time solvable in all three models, the complexity of deciding whether a
k
-stable matching exists depends on

\(\frac{k}{n}\)

and is characteristic of each model.
A road-map to Readily Available Early Validation & Verification of System Behaviour in Model-Based Systems Engineering using Software Engineering Best Practices
Authors: Cederbladh Johan , Cicchetti Antonio , Jongeling Robbert
Published: December 2024

In this article we discuss how we can facilitate the growing need for
early
validation and verification (V&V) of system behaviour in Model-Based Systems Engineering (MBSyE). Several aspects, such as reducing cost and time to market, push companies towards integration of V&V methods earlier in development to support effective decision-making. One foundational methodology seeing increased attention in industry is the use of MBSyE, which brings benefits of models with well-defined syntax and semantics to support V&V activities, rather than relying on natural language text documentation. Despite their promise, industrial adoption of these practices is still challenging.

This article presents a vision for
readily available early V&V
. We present a summary of the literature on early V&V in MBSyE and position existing challenges regarding potential solutions and future investigations towards this vision. We elaborate our vision by means of challenges with a specific emphasis on early V&V of system
behaviour
. We identify three specific challenge areas: Creating and managing
Models
,
Organisational
systems engineering aspects, and early V&V
Methods
. Finally, we outline a road-map to address these categories of challenges, in which we propose the transfer of established best practices from the software engineering domain to support emerging technologies in the systems engineering domain.
Large Language Model Supply Chain: A Research Agenda
Authors: Wang Shenao , Zhao Yanjie , Hou Xinyi , Wang Haoyu
Published: December 2024

The rapid advancement of large language models (LLMs) has revolutionized artificial intelligence, introducing unprecedented capabilities in natural language processing and multimodal content generation. However, the increasing complexity and scale of these models have given rise to a multifaceted supply chain that presents unique challenges across infrastructure, foundation models, and downstream applications. This paper provides the first comprehensive research agenda of the LLM supply chain, offering a structured approach to identify critical challenges and opportunities through the dual lenses of software engineering (SE) and security & privacy (S&P). We begin by establishing a clear definition of the LLM supply chain, encompassing its components and dependencies. We then analyze each layer of the supply chain, presenting a vision for robust and secure LLM development, reviewing the current state of practices and technologies, and identifying key challenges and research opportunities. This work aims to bridge the existing research gap in systematically understanding the multifaceted issues within the LLM supply chain, offering valuable insights to guide future efforts in this rapidly evolving domain.
Odd Cycle Transversal on
P
5
-free Graphs in Polynomial Time
Authors: Agrawal Akanksha , Lima Paloma T. , Lokshtanov Daniel , Rzążewski Paweł , Saurabh Saket , Sharma Roohani
Published: December 2024

An
independent set
in a graph

\(G\)

is a set of pairwise non-adjacent vertices. A graph

\(G\)

is
bipartite
if its vertex set can be partitioned into two independent sets. In the
Odd Cycle Transversal
problem, the input is a graph

\(G\)

along with a weight function
w
associating a rational weight with each vertex, and the task is to find a minimum weight vertex subset

\(S\)

in

\(G\)

such that

\(G-S\)

is bipartite; the weight of

\(S\)

,

\(\text{w}(S)=\sum_{v\in S}\text{w}(v)\)

. We show that
Odd Cycle Transversal
is polynomial-time solvable on graphs excluding

\(P_{5}\)

(a path on five vertices) as an induced subgraph. The problem was previously known to be polynomial-time solvable on

\(P_{4}\)

-free graphs and
NP
-hard on

\(P_{6}\)

-free graphs [Dabrowski, Feghali, Johnson, Paesani, Paulusma and Rzążewski, Algorithmica 2020]. Bonamy, Dabrowski, Feghali, Johnson and Paulusma [Algorithmica 2019] posed the existence of a polynomial-time algorithm on

\(P_{5}\)

-free graphs as an open problem. This was later re-stated by Rzążewski [Dagstuhl Reports, 9(6): 2019], by Chudnovsky, King, Pilipczuk, Rzążewski, and Spirkl [SIDMA 2021] who gave an algorithm with running time

\(n^{O(\sqrt{n})}\)

for the problem, and by Agrawal, Lima, Lokshtanov, Saurabh, and Sharma [SODA 2024] who gave a quasi-polynomial time algorithm.
RFC4 confers radioresistance of esophagus squamous cell carcinoma through regulating DNA damage response
Authors: Yang Tao , Fan Yue , Bai Guang , Huang Yinpeng
Published: December 2024

Our research indicates that replication factor C4 (RFC4) plays a role in conferring radioresistance to esophageal squamous cell carcinoma (ESCC) by bolstering DNA damage repair, primarily through the inhibition of the p53 signaling pathway. This finding positions RFC4 as a promising therapeutic target for combating radioresistance in ESCC, although further research is required to fully comprehend its intricate role in the disease.
Growth Performance, Immune Modulation, and Gene Expression Enhancement in Labeo rohita Through Integrated Probiotic Bacillus licheniformis and Phytobiotic Cinnamomum verum Strategies
Authors: Majeed Iqra , Yaqub Atif , Ayub Muhammad
Published: December 2024

This study examines the dietary application of probiotic Bacillus licheniformis and phytobiotic Cinnamomum verum concerning growth, immunity, gene expression, and disease resistance in Labeo rohita fish. A controlled experiment was conducted over 12 weeks involving 800 fingerlings, which were divided into seven groups: one control group and three groups each receiving varying doses of B. licheniformis (D1 = 105, D2 = 107, and D3 = 109 CFU/g) and C. verum (D4 = 25, D5 = 50, and D6 = 75 mg/kg) individually, along with a group with no additions (control). Growth was measured in terms of weight gain (WG), specific growth rate (SGR), feed conversion ratio (FCR), and protein efficiency ratio (PER) alongside hematology and immunology. To evaluate resistance of the test organisms, pathogenic challenge with Aeromonas hydrophila was performed. The findings indicated that fish in the D3 group achieved the highest average final weight of 125.40 ± 0.1 g, a weight increment of 86.40 ± 0.53 g, and the most favorable FCR of 0.81 ± 0.01. The D6 group followed, in contrast to the control group, which had a body weight of 95.20 ± 0.2 g, a WG of 56.73 ± 0.05 g, and a FCR of 1.03 ± 0.06. The survival rates following the challenge were analyzed, revealing that group D3 exhibited the highest effectiveness (p < 0.001). The evaluation of immunological parameters in D3 indicated increased levels of total protein, immunoglobulin M (IgM), complement component 3 (C3), and lysozyme activity relative to D1 and D2. Analysis of gene expression revealed that interleukin‐1β (IL‐1β) and tumor necrosis factor α (TNF‐α) were upregulated in the liver and head kidney tissues of fish in the D3 and D6 groups. Bacillus licheniformis, when administered at 109 CFU/g, enhances growth, feed utilization efficiency, immunity, and disease resistance in L. rohita. Cinnamomum verum at a dosage of 75 mg/kg improved the immune response. This study supports the consumption of probiotics and phytobiotics as substitutes for antibiotics in aquaculture.
Recent Developments in Recirculating Aquaculture Systems: A Review
Authors: Gupta Shruti , Makridis Pavlos , Henry Ingrid , Velle-George Michael , Ribicic Deni , Bhatnagar Amit , Skalska-Tuomi Kinga , Daneshvar Ehsan , Ciani Elia , Persson David , Netzer Roman
Published: December 2024

This article presents the recent advancements in recirculating aquaculture systems (RAS). The review explores new developments and potential future breakthroughs in RAS systems across leading countries. It highlights technical and technological advancement in plant management aimed at improving water quality, production efficiency, and animal welfare. A significant aspect of recent progress is the integration of artificial intelligence (AI), which is being used to optimize system performance, enhance monitoring, and support more precise and predictive management strategies. The review also addresses advancements in pathogen control and the prevention of disease outbreaks. Specific case studies of cutting‐edge RAS systems from different parts of the world are discussed. The review also investigates how the improvements in RAS technology can help mitigate environmental impact. Finally, the paper focuses on advancements in the production of six fish species farmed in Europe, namely Atlantic salmon (Salmo salar), European seabass (Dicentrarchus labrax), gilthead seabream (Sparus aurata), yellowtail kingfish (Seriola lalandi), arctic charr (Salvelinus alpinus), and rainbow trout (Oncorhynchus mykiss). This review is part of the ERA‐NET BlueBio cofound‐funded project titled “Optimizing land‐based fish production in next generation digital recirculating aquaculture systems,” which is focusing on the above‐mentioned fish species.
DJ‐1 as a Novel Therapeutic Target for Mitigating Myocardial Ischemia–Reperfusion Injury
Authors: Zhou Jia-Bin , Wei Tian-Peng , Wu Dan , Zhou Feng , Wang Ru-Xing
Published: December 2024

Ischemic heart disease (IHD) remains one of the most prominent causes of mortality and morbidity globally, and the risk of ischemia–reperfusion injury is becoming more severe and constant. This underscores the need to develop new methods to protect the heart from damage. DJ‐1 is a multifunctional intracellular protein encoded by the PARK7 gene that plays roles in processes including the control of autophagy, the preservation of mitochondrial integrity, the prevention of apoptosis, and the elimination of oxidative stress. DJ‐1 has recently been the focus of growing interest as a target molecule relevant to treating myocardial ischemia–reperfusion injury due to its protective properties and its role in cellular response mechanisms. Consistently, DJ‐1‐related interventions, such as its exogenous administration or the use of pharmacological agents, have been demonstrated to help protect the myocardium from ischemia–reperfusion injury and associated adverse outcomes. This review provides an overview of DJ‐1 and its therapeutic relevance in the myocardium in the setting of ischemia and reperfusion.
Boussinesq‐Like Equations: A Class of Soliton Solutions Occurs in Coastal and Ocean Engineering
Authors: Koç Dilara A. , Ismael Hajar F. , Bulut Hasan , Shah Nehad Ali , Ahmed Shams Forruque
Published: December 2024

The Boussinesq equation describes water with small amplitudes and long waves, which is one of the most famous nonlinear evolution equations. Boussinesq‐type equations have become crucial for predicting wave transformations in coastal areas since dispersion, time dependence, and weak nonlinearity terms are included in the equation. Here, the Boussinesq‐like equations by using the (m + 1/G′)‐expansion approach are investigated. In this work, we try to offer complexiton solutions to the studied types of Boussinesq equations and reveal the efficiency of this method to construct soliton solutions. The exact solutions for the Boussinesq‐like equations, including spatiotemporal dispersion, are computed using this method. Complexiton traveling wave solutions in the forms of kink, singular, periodic, and periodic‐lump are obtained through calculations. The graphs of these solutions are drawn and analyzed to better understand and analyze these gained solutions. Moreover, the existence of all solutions is verified, and to our knowledge, the solutions are novel.
Oral Etoposide for Relapsed or Refractory Ewing Sarcoma in Adolescent and Adult Patients
Authors: Kostos Louise , Rayson Victoria , Desai Jayesh , Orme Lisa , Bae Susie , Hamilton Anne , Luen Stephen J. , Lewin Jeremy
Published: December 2024

Prognosis remains poor for patients with relapsed or refractory Ewing sarcoma, with limited treatment options after first‐line therapy. Oral etoposide has efficacy in the paediatric setting; however, data are limited in adults. A retrospective analysis was conducted on 33 patients with relapsed or refractory Ewing sarcoma who completed at least one cycle of oral etoposide at the Peter MacCallum Cancer Centre from 2005 to 2020. The median age at diagnosis and first relapse was 21 and 23 years, respectively. All patients had prior exposure to intravenous etoposide. Nine patients (27%) had stable disease for at least 6 months, and six patients (18%) had a partial response. The clinical benefit rate was 45%. The median PFS was 3.6 months (95% CI: 1.7–5.5), and OS was 8.5 months (95% CI: 4.1–13.0). Despite prior exposure, oral etoposide demonstrated antitumour activity and durable responses in the relapsed or refractory setting for adult patients with Ewing sarcoma.
Phase 1/2 Study of the Indoleamine 2,3-Dioxygenase 1 Inhibitor Linrodostat Mesylate Combined with Nivolumab or Nivolumab and Ipilimumab in Advanced Solid Tumors or Hematologic Malignancies
Authors: Luke Jason J. , Gelmon Karen , Siu Lillian L. , Moreno Victor , Desai Jayesh , Gomez-Roca Carlos A. , Carlino Matteo S. , Pachynski Russell K. , Cosman Rasha , Chu Quincy Siu-Chung , Damian Silvia , Curigliano Giuseppe , Tam Rachel , Wang Xianling , Jeyamohan Chandrika , Wang Lily , Zhu Li , Santucci-Pereira Julia , Greenawalt Danielle M. , Tabernero Josep
Published: December 2024

Purpose:

To evaluate the safety, efficacy, pharmacokinetics, pharmacodynamics, and biomarkers of linrodostat mesylate, a selective, oral indoleamine 2,3-dioxygenase 1 inhibitor combined with nivolumab ± ipilimumab in advanced solid tumors and hematologic malignancies.

Patients and Methods:

In this phase 1/2 study, patients received once-daily linrodostat [part 1 (escalation), 25–400 mg; part 2 (expansion), 100 or 200 mg] plus nivolumab (480 mg every 4 weeks or 240 mg every 2 weeks) or triplet therapy (part 3, linrodostat 20–100 mg once daily; nivolumab 360 mg every 3 weeks or 480 mg every 4 weeks; ipilimumab 1 mg/kg every 6 weeks or every 8 weeks). Endpoints included safety and efficacy (coprimary; parts 2 and 3), pharmacokinetics, pharmacodynamics, biomarkers, and efficacy (part 1).

Results:

A total of 55, 494, and 41 patients were enrolled in parts 1, 2, and 3, respectively. Linrodostat exposures exceeded predicted therapeutic target concentrations starting at 50 mg. Rates of grade 3/4 adverse events were 50.1% to 63.4%. The maximum tolerated linrodostat dose was 200 mg; dose-limiting toxicities were primarily immune-related. Responses were observed across different cohorts, study parts, and tumor types, particularly in immunotherapy-naïve patients. Kynurenine decreased with linrodostat + nivolumab regardless of response. In contrast, IFN-γ gene expression signature was associated with response; in nonmelanoma patients, a composite of low tryptophan 2,3-dioxygenase gene expression plus high IFN-γ signature was associated with response.

Conclusions:

Linrodostat + nivolumab ± ipilimumab demonstrated a manageable safety profile. Kynurenine changes supported indoleamine 2,3-dioxygenase 1 pathway inhibition but did not correlate with response. A composite biomarker of low tryptophan 2,3-dioxygenase expression plus high IFN-γ gene expression may predict response to linrodostat + nivolumab.
Complete Remissions of HER2-Positive Trastuzumab-Resistant Xenografts Using a Potent [225Ac]Ac-Labeled Anti-HER2 Antibody–Drug Radioconjugate
Authors: Pougoue Ketchemen Jessica , Njotu Fabrice Ngoh , Babeker Hanan , Monzer Alissar , Nwangele Emmanuel , Tikum Anjong Florence , Henning Nikita , Hassani Nava , Frye Sarah , Perron Randy , Byrne Chris , Didychuk Candice , Qi Qi , Bannister Laura , Doroudi Alireza , Fonge Humphrey
Published: December 2024

Purpose:

There is overwhelming interest to use actinium-225 ([225Ac]Ac) to develop targeted α therapies. Antibody–drug conjugates (ADC) are highly cytotoxic. Combining [225Ac]Ac with an ADC to develop an antibody–drug radioconjugate [225Ac]Ac–macropa–trastuzumab(T)–PEG6–emtansine (DM1), is expected to be more effective than its ADC (T–PEG6–DM1) against breast cancer.

Experimental Design:

[89Zr]Zr–p-isothiocyanatobenzyl desferrioxamine (DFO)–T–PEG6–DM1 (imaging) and [225Ac]Ac–macropa–T–PEG6–DM1 (radiotherapy) were developed. Biodistribution and safety evaluations of [225Ac]Ac–macropa–T-PEG6–DM1 were carried out in non–tumor-bearing BALB/c mice. MicroPET imaging and biodistribution were done using [89Zr]Zr-DFO–T–PEG6–DM1, and radiotherapy using [225Ac]Ac–macropa–T–PEG6–DM1 was carried out in athymic BALB/c nude mice bearing trastuzumab-resistant HCC1954 and trastuzumab-DM1 (T-DM1)/trastuzumab-resistant JIMT-1 tumor-bearing mice.

Results:

After 7 days of incubation at 37°C, [225Ac]Ac–macropa–T–PEG6–DM1 was stable in both human serum (89.2% ± 0.9%) and PBS (82.8% ± 0.4%). T–PEG6–DM1 (8 mg/kg) and [225Ac]Ac–macropa–T–PEG6–DM1 (3 × 18 kBq) administered separately in non–tumor-bearing mice 10 days apart were well tolerated biochemically and hematologically. Imaging and biodistribution showed high tumor uptake of [89Zr]Zr-DFO–T–PEG6–DM1 in tumor-bearing mice at 120 hours after injection: 38.1% ± 2.8% IA/g (HCC1954) and 14.6% ± 1% IA/g (JIMT-1). In HCC1954 tumor-bearing mice, all treatment groups had complete remission (8/8), indicative of the responsiveness of the xenograft to T-DM1–based treatments, whereas for JIMT-1 xenografts (having 1/8 complete remission) at 23 days after treatment, tumor volumes were 332.1 ± 77.5 vs. 244.6 ± 63 vs. 417.9 ± 62.1 vs. 102.4 ± 18.5 for the saline (negative control), T-DM1 (positive control), T–PEG6–DM1, and [225Ac]Ac–macropa–T–PEG6–DM1, respectively.

Conclusions:

[225Ac]Ac–macropa–T–PEG6–DM1 is more potent than ADC against trastuzumab-resistant breast cancer and necessitates clinical translation.