bluuebunny/crossref_metadata_2025 huggingface dataset:
A double‐blinded randomised control study to compare the effectiveness and safety of intralesional vitamin D3 with intralesional triamcinolone and its correlation with tissue expression of vitamin D receptors in patients with keloid
Authors: Goyal Aman , Mehta Hitaishi , Narang Tarun , Vinay Keshavamurthy , Chhabra Seema , Shilpa  , Kaushik Hitaishi , Kaur Manjot , Sachdeva Naresh , Dogra Sunil
Published: September 2024

Intralesional steroids commonly used for keloid treatment have adverse effects like cutaneous atrophy and telangiectasias. Safer and more effective therapies are needed. Preliminary studies suggest intralesional vitamin D as a potential alternative treatment. The aim of this study was to compare efficacy and safety of intralesional vitamin D with triamcinolone for keloids, and correlate tissue expression of vitamin D receptors (VDRs) with treatment outcomes. Sixty patients were randomly assigned to two groups: Group A (intralesional vitamin D) and Group B (intralesional triamcinolone). Four injections were given at 4‐week intervals, with an 8‐week follow‐up. Biopsies were taken pre‐ and post‐treatment to examine VDR expression levels and treatment response correlation. The primary outcome of interest was the proportion of patients achieving a 50% reduction in Vancouver Scar Scale (VSS). Secondary outcomes included incidence of adverse effects, and changes in VDR expression before and after treatment. Baseline VSS scores were 9.73 ± 1.01 (vitamin D group) and 10.13 ± 1.07 (triamcinolone group). After treatment, mean VSS decreased to 5.17 ± 0.59 (vitamin D group, p < 0.001) and 4.77 ± 0.77 (triamcinolone group, p < 0.001), with significantly better response in latter (p = 0.03). More than 50% reduction in VSS score was higher in the triamcinolone group (76.7% vs. 50%, p = 0.032). No recurrences were noted during the 8‐week follow‐up. Hypopigmentation (80% vs. 36.7%, p < 0.001) and atrophy (73.3% vs. 40%, p = 0.009) were more common in the triamcinolone group. No significant difference in pre‐ and post‐treatment VDR receptor expression was observed in either group. Both triamcinolone acetonide and vitamin D were effective for keloids. Triamcinolone was more efficacious, whereas vitamin D was safer, suggesting it as a viable alternative for keloid management.
Measurement of respiratory–swallowing coordination using an oronasal facemask in healthy individuals
Authors: Cross Elizabeth , Guiu Hernandez Esther , Macrae Phoebe
Published: September 2024

Respiratory–swallowing coordination (RSC) is well established as an essential airway‐protective mechanism. Previous studies have used nasal airflow and/or kinematic rib cage and abdominal measures to assess respiration surrounding swallowing, meaning that the direct influence of oral respiration on RSC remains unknown. This study used a partitioned oronasal facemask to compare respiratory phase patterns measured using isolated nasal airflow with those measured using combined oronasal airflow during non‐ingestive and ingestive swallowing tasks. Twenty‐four healthy individuals with no respiratory or swallowing disorders were assessed at rest and during cued dry, 10 mL water, continuous drinking and cracker swallowing tasks. Respiratory phase patterns were determined for discrete swallows using the nasal and combined oronasal channels separately. There was variable agreement between respiratory phase patterns according to the nasal and oronasal channels across swallowing conditions. The frequency of exhale–swallow–exhale, inhale–swallow–exhale and exhale–swallow–inhale patterns increased by 2%–3% each with the addition of oral flow data to nasal data, whereas the prevalence of inhale–swallow–inhale and ambiguous patterns decreased. This suggests that estimates of respiratory phase patterns are altered minimally by inclusion of oral respiratory estimates in a healthy sample. There were several additional findings of note, including lower within‐participant, within‐session trial consistency (test–retest reliability) than expected, suggesting high variability in respiratory phase patterns across trials. Additionally, data showed evidence of swallowing non‐respiratory flow at the beginning and end of the respiratory–swallowing pause, moving in both inward and outward directions, potentially expanding current understanding of swallowing non‐respiratory flow. Further in‐depth physiological investigations are required to improve understanding of these findings.
Synbiotic supplementation ameliorates anxiety and myocardial ischaemia–reperfusion injury in hyperglycaemic rats by modulating gut microbiota
Authors: Bulut Erman Caner , Erol Kutucu Deniz , Üstünova Savaş , Ağırbaşlı Mehmet , Dedeakayoğulları Huri , Tarhan Çağatay , Kapucu Ayşegül , Yeğen Berrak Ç. , Demirci Tansel Cihan , Gürel Gürevin Ebru
Published: September 2024

Hyperglycaemia, hyperlipidaemia, hypertension and obesity are the main risk factors affecting the development and prognosis of ischaemic heart disease, which is still an important cause of death today. In our study, male Sprague–Dawley rats were fed either a standard diet (SD) or a high fat and high carbohydrate diet (HF‐HCD) for 8 weeks and streptozotocin (STZ) was injected at the seventh week of the feeding period. In one set of rats, a mixture of a prebiotic and probiotics (synbiotic, SYN) was administered by gavage starting from the beginning of the feeding period. Experimental myocardial ischaemia–reperfusion (30 min/60 min) was induced at the end of 8 weeks. Hyperglycaemia, hypertension and increased serum low‐density lipoprotein levels occurred in SD‐ and HF‐HCD‐fed and STZ‐treated rats followed for 8 weeks. Increased density of the Proteobacteria phylum was observed in rats with increased blood glucose levels, indicating intestinal dysbiosis. The severity of cardiac damage was highest in the dysbiotic HF‐HCD‐fed hyperglycaemic rats, which was evident with increased serum creatine kinase‐MB (CK‐MB), cardiac troponin I (cTnI), tumour necrosis factor‐α, and interleukin‐6 levels, along with a decrease in ST‐segment resolution index. SYN supplementation to either a normal or a high‐fat high‐carbohydrate diet improved gut dysbiosis, reduced anxiety, decreased CK‐MB and cTnI levels, and alleviated myocardial ischaemia–reperfusion injury in hyperglycaemic rats.
Computational Fluid Dynamics Modeling of Additively Manufactured Extreme Environment Heat Exchangers for Waste Heat Recuperation
Authors: Duggirala Vyas , Reddy Venkateswara , Muley Arun , Stoia Micheal , Vanaffelen Doug
Published: September 2024

Advanced Brayton cycle-based waste heat recovery (WHR) system for a targeted energy efficiency of 20–50% and gravimetric power densities of 1.6–1.9 kW/kg are attractive propositions for future airplane designs. One of the critical challenges for the maturation of these technologies is the need to achieve highly compact heat exchangers (HX) capable of operation under extreme pressure and temperature environments. The current work presents computational fluid dynamics (CFD) modeling strategies for the design and development of additively manufactured extreme environment heat exchangers (EEHX). Modeling and simulation-driven design improvements to the HX are implemented to achieve a power density of 15 kW/kg under the extreme environment of 800 °C inlet temperature and 80 bar pressure with supercritical CO2 as the working fluid. Various CFD-based modeling methods are described, starting from selecting, rating, and sizing heat transfer (HT) surfaces, followed by detailed core modeling through periodic and end-section models. Further, a novel porous media-based modeling approach with a high-fidelity manifold model is implemented to generate optimal manifold profiles while minimizing flow maldistribution through the core. Comprehensive physical testing of the additively manufactured heat exchanger prototypes has been used to validate the developed numerical models within 5–10% of pressure drop and heat transfer predictions.
Acute and Chronic Effects of Interval Aerobic Exercise on Hepcidin, Ferritin, and Liver Enzymes in Adolescents With Beta-Thalassemia Major
Authors: Mohabbat Majid , Barati Amir Hossein , Azarkeivan Azita , Eghbali Ehsan , Arazi Hamid
Published: September 2024

Purpose: This study aimed to determine the acute and chronic effects of interval aerobic exercise on hepcidin, ferritin, and liver enzymes in adolescents with beta-thalassemia major. Methods: Twenty-six beta-thalassemia major adolescents referred to the Thalassemia Clinic and Research Center were selected as study participants and randomly divided into control (n = 13) and training (n = 13) groups. Participants performed 3 sessions per week for 45 minutes in each session for 8 weeks of aerobic interval exercise with an intensity of 50% to 65% of the heart rate reserve. Blood samples were taken before, immediately after the exercise session, and 48 hours after the last training session, and liver enzymes aspartate aminotransferase, alanine aminotransferase (ALT), alkaline phosphatase (ALP), ferritin, and hepcidin were evaluated. Results: The results showed a decrease in aspartate aminotransferase, ALT, ALP, ferritin, and hepcidin levels due to 8 weeks of aerobic interval training (P = .14, P = .97, P = .03, P < .001, P < .001; respectively). Intergroup changes in all variables except ALT and hepcidin were significant (P < .05). Besides, acute aerobic exercise increased levels of aspartate aminotransferase, ALT, ferritin, and hepcidin (P = .04, P = .52, P < .001, P < .001; respectively), whereas ALP levels decreased (P < .001). In addition, changes in ALP and hepcidin levels were significant between the 2 groups (P = .05, P < .001; respectively). Conclusion: Based on the study’s results, it can be concluded that 8 weeks of aerobic interval training can decrease ferritin and hepcidin levels, but acute aerobic exercise increases them.
Transcripts of repetitive DNA elements signal to block phagocytosis of hematopoietic stem cells
Authors: Pessoa Rodrigues Cecilia , Collins Joseph M. , Yang Song , Martinez Catherine , Kim Ji Wook , Lama Chhiring , Nam Anna S. , Alt Clemens , Lin Charles , Zon Leonard I.
Published: September 2024

Macrophages maintain hematopoietic stem cell (HSC) quality by assessing cell surface Calreticulin (Calr), an “eat-me” signal induced by reactive oxygen species (ROS). Using zebrafish genetics, we identified Beta-2-microglobulin (B2m) as a crucial “don’t eat-me” signal on blood stem cells. A chemical screen revealed inducers of surface Calr that promoted HSC proliferation without triggering ROS or macrophage clearance. Whole-genome CRISPR-Cas9 screening showed that Toll-like receptor 3 (Tlr3) signaling regulated
b2m
expression. Targeting
b2m
or
tlr3
reduced the HSC clonality. Elevated B2m levels correlated with high expression of repetitive element (RE) transcripts. Overall, our data suggest that RE-associated double-stranded RNA could interact with TLR3 to stimulate surface expression of B2m on hematopoietic stem and progenitor cells. These findings suggest that the balance of Calr and B2m regulates macrophage-HSC interactions and defines hematopoietic clonality.
Mega El Niño instigated the end-Permian mass extinction
Authors: Sun Yadong , Farnsworth Alexander , Joachimski Michael M. , Wignall Paul B. , Krystyn Leopold , Bond David P. G. , Ravidà Domenico C. G. , Valdes Paul J.
Published: September 2024

The ultimate driver of the end-Permian mass extinction is a topic of much debate. Here, we used a multiproxy and paleoclimate modeling approach to establish a unifying theory elucidating the heightened susceptibility of the Pangean world to the prolonged and intensified El Niño events leading to an extinction state. As atmospheric partial pressure of carbon dioxide doubled from about 410 to about 860 ppm (parts per million) in the latest Permian, the meridional overturning circulation collapsed, the Hadley cell contracted, and El Niños intensified. The resultant deforestation, reef demise, and plankton crisis marked the start of a cascading environmental disaster. Reduced carbon sequestration initiated positive feedback, producing a warmer hothouse and, consequently, stronger El Niños. The compounding effects of elevated climate variability and mean state warming led to catastrophic but diachronous terrestrial and marine losses.
Durably reducing conspiracy beliefs through dialogues with AI
Authors: Costello Thomas H. , Pennycook Gordon , Rand David G.
Published: September 2024

Conspiracy theory beliefs are notoriously persistent. Influential hypotheses propose that they fulfill important psychological needs, thus resisting counterevidence. Yet previous failures in correcting conspiracy beliefs may be due to counterevidence being insufficiently compelling and tailored. To evaluate this possibility, we leveraged developments in generative artificial intelligence and engaged 2190 conspiracy believers in personalized evidence-based dialogues with GPT-4 Turbo. The intervention reduced conspiracy belief by ~20%. The effect remained 2 months later, generalized across a wide range of conspiracy theories, and occurred even among participants with deeply entrenched beliefs. Although the dialogues focused on a single conspiracy, they nonetheless diminished belief in unrelated conspiracies and shifted conspiracy-related behavioral intentions. These findings suggest that many conspiracy theory believers can revise their views if presented with sufficiently compelling evidence.
No ‘collapse’ for ancient people on Rapa Nui
Authors: Ortega Rodrigo Peréz
Published: September 2024

New genomic, archaeological evidence counters influential tale of ecological suicide
The OprF porin as a potential target for the restoration of carbapenem susceptibility in
Pseudomonas aeruginosa
expressing acquired carbapenemases
Authors: Nordmann Patrice , Helsens Nicolas , Poirel Laurent , Sadek Mustafa , Bumann Dirk , Findlay Jacqueline
Published: September 2024

Carbapenem resistance in
Pseudomonas aeruginosa
is primarily due to the acquisition of carbapenemases and is often associated with a diminution of the membrane permeability. The outer membrane protein, OprD, is a well-known route, by which carbapenems, predominantly imipenem, can enter the cell, and its loss has been associated with reduced susceptibility to imipenem. In this study, we investigated the antibiotic susceptibility patterns of isogenic
P. aeruginosa
mutants containing various acquired β-lactamases, including carbapenemases, in a porin-depleted background. We identified that the deletion of
oprF
was associated with some recovery of susceptibility to carbapenems.
L-tryptophan and copper interactions linked to reduced colibactin genotoxicity in
pks+ Escherichia coli
Authors: Bayne Charlie , Boutard Magali , Zaplana Tom , Tolonen Andrew C.
Published: September 2024

Colibactin, a nonribosomal peptide/polyketide produced by
pks+ Enterobacteriaceae
, is a virulence factor and putative carcinogen that damages DNA by interstrand crosslinking (ICL). While the
clb
genes for colibactin biosynthesis have been identified, studies are needed to elucidate the mechanisms regulating colibactin production and activity. Here we perform untargeted metabolomics of
pks+ Escherichia
coli cultures to identify L-tryptophan as a candidate repressor of colibactin activity. When
pks+ E. coli
is grown in a minimal medium supplemented with L-tryptophan
in vitro
ICL of plasmid DNA is reduced by >80%. L-tryptophan does not affect the transcription of
clb
genes but protects from copper toxicity and triggers the expression of genes to export copper to the periplasm where copper can directly inhibit the ClbP peptidase domain. Thus, L-tryptophan and copper interact and repress colibactin activity, potentially reducing its carcinogenic effects in the intestine.

IMPORTANCE

Colibactin is a small molecule produced by
pks
+
Enterobacteriaceae
that damages DNA, leading to oncogenic mutations in human genomes. Colibactin-producing
Escherichia coli
(
pks
+) cells promote tumorigenesis in mouse models of colorectal cancer (CRC) and are elevated in abundance in CRC patient biopsies, making it important to identify the regulatory systems governing colibactin production. Here, we apply a systems biology approach to explore metabolite repression of colibactin production in
pks
+
E. coli
. We identify L-tryptophan as a repressor of colibactin genotoxicity that stimulates the expression of genes to export copper to the periplasm where it can inhibit ClbP, the colibactin-activating peptidase. These results work toward an antibiotic-sparing, prophylactic strategy to inhibit colibactin genotoxicity and its tumorigenic effects in the intestine.
Evolution of the Tn
4371
ICE family:
traR
-mediated coordination of cargo gene upregulation and horizontal transfer
Authors: Matsumoto Satoshi , Kishida Kouhei , Nonoyama Shouta , Sakai Keiichiro , Tsuda Masataka , Nagata Yuji , Ohtsubo Yoshiyuki
Published: September 2024

ICE
KKS102
Tn
4677
carries a
bph
operon for the mineralization of polychlorinated biphenyls (PCBs)/biphenyl and belongs to the Tn
4371
ICE (integrative and conjugative element) family. In this study, we investigated the role of the
traR
gene in ICE transfer. The
traR
gene encodes a LysR-type transcriptional regulator, which is conserved in sequence, positioning, and directional orientation among Tn
4371
family ICEs. The
traR
belongs to the
bph
operon, and its overexpression on solid medium resulted in modest upregulation of
traG
(threefold), marked upregulation of
xis
(80-fold), enhanced ICE excision and, most notably, ICE transfer frequency. We propose the evolutional roles of
traR
, which upon insertion to its current position, might have connected the cargo gene activation and ICE transfer. This property of ICE, i.e., undergoing transfer under environmental conditions that lead to cargo gene activation, would instantly confer fitness advantages to bacteria newly acquiring this ICE, thereby resulting in efficient dissemination of the Tn
4371
family ICEs.

IMPORTANCE

Only ICE
KKS102
Tn
4677
is proven to transfer among the widely disseminating Tn
4371
family integrative and conjugative elements (ICEs) from β and γ-proteobacteria. We showed that the
traR
gene in ICE
KKS102
Tn
4677
, which is conserved in the ICE family with fixed location and direction, is co-transcribed with the cargo gene and activates ICE transfer. We propose that capturing of
traR
by an ancestral ICE to the current position established the Tn
4371
family of ICEs. Our findings provide insights into the evolutionary processes that led to the widespread distribution of the Tn
4371
family of ICEs across bacterial species.
Supplemental Material: The geometry of fault reactivation and uplift along the central part of the Maacama Fault Zone, Northern California Coast Ranges
Authors: Melosh B.L. , al. et
Published: September 2024

Figure A1 (interactive version of Figure 7). Results of the geomorphic analysis of the northern Mayacamas Mountains. Use radio buttons to view sections A–D. (A) Channel steepness index map; elevated values are shown by brighter colors, and basin numbers 1 through 14 correspond to subfigures B and C, Figure 8, and mentions throughout the text. Hillshade is from NASA Shuttle Radar Topography Mission (2013). (B) Chi map with brighter colors representing greater chi values; chi gradients are identified where adjacent basins have disparate chi values at their uppermost reaches. (C) Concavity index map displaying concavity results for each basin; lighter colors indicate lower concavity, labels are basin #: concavity value. (D) Geologic map presented in Figure 2 is included here for easy reference to identify areas where rock hardness may impact geomorphic results. Sp—sheared serpentinite lens; UCMA—Ukiah–Cow Mountain antiform; MMS—Middle Mountain Synform; WCF—Willow Creek Fault. 
Severe lupus nephritis in a young adult with PTEN hamartoma tumour syndrome
Authors: Drozdz Wiktoria , Joller Daniel , Grosse Philipp , Fehr Thomas
Published: September 2024

On chromosome 10q23 is found thePTENgene, which encodes a phosphate and tension homologue. The protein dephosphorylates phosphatidylinositol-(3,4,5)-trisphosphate at the plasma membrane to produce inorganic phosphatidylinositol-(4,5)-bisphosphate. This enzymatic activity inhibits the phosphatidylinositol-3-kinase, protein kinase B and mammalian target of the rapamycin signalling cascade. Consequently, essential cellular functions, including metabolic regulation, cellular growth, proliferation and viability, are affected. A mutation in this gene gives rise to hamartoma tumour syndrome, which exhibits a range of phenotypes, including Bannayan-Riley-Ruvalcaba syndrome, Cowden syndrome and proteus-like disease. A man in his late 20s with a PTEN tumour-like arteriovenous malformation in the right thigh was recently diagnosed with lupus nephritis. The patient’s nephritic symptoms, pleural effusion, dyslipidaemia and splenomegaly demonstrate systemic lupus erythematosus (SLE) multisystem involvement. The case report identifies an association between a PTEN mutation and a new diagnosis of SLE that might have been triggered by PTEN-associated immune dysregulation.
Utilisation of a balloon-mounted coronary stent in the treatment of a patient with petrous carotid artery dissection
Authors: Atiiga Peter , Lakshminarayan Raghuram , Nejadhamzeeigilani Hamed
Published: September 2024

A man in his 50s presented with acute left-sided weakness, facial drooping and slurred speech, suggestive of a major stroke. Imaging revealed a complete blockage in the right internal carotid artery (ICA) due to dissection. Perfusion studies showed a significant area at risk of infarction. Attempted navigation of standard carotid stents failed due to the tortuosity of the ICA. A balloon-mounted coronary stent was successfully deployed in the petrous ICA segment, restoring blood flow. A follow-up MRI confirmed stent patency, and the patient achieved complete recovery with return to baseline function. Symptomatic carotid artery dissections can be treated with stenting to prevent strokes, however, tortuous ICAs in distal dissections pose a technical challenge. Balloon-mounted coronary stents, though not approved for this use, can offer a feasible solution. This case highlights the need for further research and development of devices for managing dissections in distal locations in tortuous ICAs.
Coexistence of pulmonary thromboembolism and pulmonary tuberculosis: a diagnostic dilemma
Authors: Shanker Ajay , Mandya Thimmaiah Chandramouli , Baikunje Nandakishore , Nair Nandu
Published: September 2024

A man in his early 50s with previously treated pulmonary tuberculosis (TB) presented with a 3-month history of cough, expectoration and progressive breathlessness, accompanied by significant weight loss. Examination revealed tachycardia, tachypnoea, hypoxaemia and unilateral diminished breath sounds. Investigations showed anaemia, leucocytosis and a homogeneous opacity on the left side of the CXR. ECG and echocardiography suggested pulmonary thromboembolism (PTE). A CT pulmonary angiogram confirmed a chronic embolus and a severely fibrosed left lung. A comprehensive thrombophilia workup yielded normal results and the PTE was attributed to his history of TB. Sputum analysis confirmed reactivated TB, leading to the initiation of antitubercular therapy. The patient improved clinically with plans for a repeat CT pulmonary angiography to assess the need for pulmonary thromboendarterectomy after completing TB treatment. This case highlights the possible association of TB and PTE, its management and why it should be considered as a differential diagnosis in patients with a history of TB presenting with exacerbated breathlessness.
COVID-19 autism spectrum disorder-like transient neurocognitive clinical presentation
Authors: Selim Basma , Satti Alia , Abdelgadir Ibtihal Siddiq
Published: September 2024

The COVID-19 pandemic has impacted the general population in different ways, including the vulnerable population of children with special needs.

In this case report, we will discuss the emergence of a transient, full-blown picture of autism spectrum disorder (ASD) in a child who contracted a COVID-19 infection, and his gradual improvement over the course of a few months. This broadens our perspective on the possible neurocognitive clinical presentations of COVID-19 infection.
Surgical management of rare hepatobiliary sarcomas in a regional teaching hospital: a collaborative model for optimal care with case studies
Authors: Ng Irene Ai Ting , Tan Hiang Jin , Chiow Adrian Kah Heng , Nita Thiruchelvam
Published: September 2024

Sarcomas are challenging and conventionally referred to sarcoma specialist centres. In select cases with required surgical expertise, collaboration with a quaternary sarcoma centre rather than an upfront transfer of care may reduce logistic challenges without compromising patient care.

We present a case series of three rare tumours of hepatobiliary origin—two cases of undifferentiated embryonal liver sarcoma in adults and one case of follicular dendritic sarcoma of the cystic lymph node.

All three patients underwent surgery in a non-sarcoma specialist centre by hepatobiliary specialist surgeons with concurrent remote referrals to a sarcoma specialist quaternary centre. Both centres belong to the same cluster. R0 resection and no significant postoperative morbidity were achieved. All three patients currently remain disease-free.

The unique and integrated healthcare systems within Singapore render cross-institution management possible. This case series suggests that an established setup for cross-centre collaboration facilitates wholistic patient care with good outcomes.
Alveolar capillary dysplasia complicated by subglottic stenosis
Authors: Nagamoto Kotaro , Maruyama Hidehiko , Ishuguro Akira , Ito Yushi
Published: September 2024

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is an interstitial lung disease. In ACDMPV, respiratory impairment with severe pulmonary hypertension occurs from the early hours of life. Anomalies in the cardiovascular, gastrointestinal and genitourinary systems have been reported. However, little is known about upper airway abnormalities. We encountered a genetically diagnosed ACDMPV infant who presented with subglottic and bronchial stenosis. The prenatal diagnosis was hypoplastic left heart syndrome. Her respiratory condition worsened at 16 hours of life. We found subglottic stenosis when intubating. She died on day 7. Autopsy imaging with CT scan showed bilateral main bronchial stenosis. Chromosomal microarray revealed a 531 kb deletion in chromosome 16q24.1, includingFOXF1.
Haemophagocytic lymphohistiocytosis secondary to disseminated histoplasmosis in a patient with leprosy
Authors: Mufarrih Syed , Lusby Heather , Watson Patricia
Published: September 2024

Multidrug therapy has significantly reduced the global burden of Hansen’s disease; however, complications from long-term treatment persist. A male resident of southern Kentucky, in his 30s and of Micronesian descent, presented with worsening abdominal pain associated with anorexia, fatigue, functional decline and occasional haemoptysis. He was compliant with multidrug therapy for leprosy. Laboratory investigations revealed pancytopenia. He was initially treated under a sepsis protocol and later switched to high-dose steroids due to a suspected immune reaction from missed corticosteroid doses. Despite aggressive treatment for refractory pancytopenia, the patient’s condition deteriorated, and he passed away from cardiac arrest. Posthumous bone marrow biopsy revealed haemophagocytic lymphohistiocytosis secondary to disseminated histoplasmosis with bone marrow infiltration. This case highlights the importance of proactive fungal screening in immunocompromised leprosy patients, particularly in endemic regions, as early detection and timely intervention can prevent severe complications.
Preferences for sexual health services among middle-aged and older adults in the UK: a discrete choice experiment
Authors: Sakuma Yoshiko , Tieosapjaroen Warittha , Wu Dan , Conyers Hayley , Shakespeare Thomas , Guigayoma John , Terris-Prestholt Fern , Pan Stephen W , Tucker Joseph D , Ong Jason , Kpokiri Eneyi
Published: September 2024

Objectives

Sexual health is an integral part of well-being. However, the sexual health needs and desires of middle-aged and older adults have been largely disregarded. Therefore, this study aimed to understand the sexual health service preferences of adults aged 45 and older to improve the accessibility of sexual health services in the UK.

Methods

The formative stage of the discrete choice experiment (DCE) followed three steps: concept elicitation, refining and implementation. The attributes and levels were determined through 22 semistructured interviews during the concept elicitation, followed by pilot testing for refining the survey. Qualtrics XM, with conjoint project features, was implemented as the DCE survey platform. We used a random parameter logit model to estimate the relative importance (RI) of each attribute and preference for each attribute level. We also used a latent class model to explore groups of participants with similar preferences.

Results

In total, 200 responses were included for analysis. The demographic breakdown included 62.5% females, 35.5% people with disabilities and 26.0% identifying as a sexual minority. The median age was 53. Preferences for using sexual health services were mainly influenced by the mode of delivery (RI 32%), location (RI 18%) and cost (RI 16%). Participants showed a preference for face-to-face interactions at sexual health clinics and displayed a willingness to pay for private services. Extra support and the consultation style played minor roles in their decision-making process. No differences in preferences were identified among disabled people. However, sexual minorities expressed their preferences for conventional messaging.

Conclusions

Our study revealed that middle-aged and older individuals prioritise sexual health services offering face-to-face consultations, emphasising a preference to attend sexual health clinics over cost. Aligning service delivery with these preferences has the potential to significantly improve the accessibility and uptake of sexual health services for adults aged 45 and older in the UK.
Sex differences in the epidemiology of spontaneous and traumatic cervical artery dissections
Authors: Schipani Elke , Griffin Kim J , Oakley Carlee I , Keser Zafer
Published: September 2024

Background

Recent studies show cervical artery dissection (CeAD) is equally common between sexes, and that the incidence of CeAD has risen at a greater rate in females than males. In this population-based study, we identify sex differences in patients diagnosed with spontaneous and traumatic CeAD.

Methods

144 patients with spontaneous or traumatic CeAD were studied for sex differences in medical comorbidities, presenting symptoms and outcomes.

Results

Females were more likely to carry a diagnosis of migraine, while males were more likely to have hyperlipidaemia. Females were more likely to present with neck pain, males with stroke. Females were significantly more likely to develop recurrent dissections in the study period.

Conclusions

These findings underscore the importance of understanding CeAD through the lens of sex differences and may explain the significant rise in the diagnosis of CeAD in females. These findings support the importance of considering sex-specific risk factors and medical comorbidities with sex predilection in the diagnosis and management of CeAD. Furthermore, it emphasises the importance of female patients understanding risk factors and presenting signs that should prompt evaluation for CeAD.
Association between ASPECTS region of infarction and clinical outcome in non-acute large vessel occlusion ischaemic stroke after endovascular recanalisation
Authors: Lu Jialiang , Lu Ziwei , Li Ye , Li Fangcun , Feng Yuxuan , Dang Meijuan , Yang Yang , Tang Fan , Li Tao , Zhao Lili , Jian Yating , Wang Xiaoya , Zhang Lei , Fan Hong , Zhang Guilian
Published: September 2024

Purpose

This study retrospectively investigated whether infarction in specific Alberta Stroke Program Early CT Score (ASPECTS) regions is associated with clinical outcome in patients with symptomatic non-acute internal carotid or middle cerebral artery occlusion who underwent endovascular recanalisation (ER).

Methods

Preoperative ASPECTS and region of infarction were recorded before recanalisation. Clinical outcome was evaluated 90 days after the procedure using the modified Rankin Scale; a score>2 was defined as poor outcome. Secondary outcomes included postprocedural cerebral oedema, intracranial haemorrhage (ICH) and symptomatic ICH.

Results

Among the 86 patients included, 90-day outcome was poor in 30 (34.9%) and 40 experienced cerebral oedema (46.5%). Multivariate logistic regression models showed that lenticular nucleus infarction (OR 19.61–26.00, p<0.05), admission diastolic blood pressure (OR 1.07–1.08, p<0.05), preprocedural National Institutes of Health Stroke Scale (OR 1.96–2.05, p<0.001) and haemorrhagic transformation (OR 14.99–18.81, p<0.05) were independent predictors of poor 90-day outcome. The area under the receiver operating characteristic curve for lenticular nucleus infarction as a predictor of poor outcome was 0.73. M2 region infarction (OR 26.07, p<0.001) and low American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology collateral circulation grade (OR 0.16, p=0.001) were independent predictors of postprocedural cerebral oedema. The area under the receiver operating characteristic curve for M2 region infarction as a predictor of cerebral oedema was 0.64. Region of infarction did not significantly differ between patients with and without postprocedural ICH or symptomatic ICH.

Conclusions

Lenticular nucleus and M2 region infarction were independent predictors of poor 90-day outcome and postprocedural cerebral oedema, respectively, in patients with non-acute anterior circulation large artery occlusion who underwent ER.
Chaos and feasibility analysis of a healthy lifestyle’s sustainability using fractional-order polycystic ovarian syndrome’s effect on infertility
Authors: Saleem Muhammad Umer , Farman Muhammad , Nisar Kottakkaran Sooppy , Raza Nauman , Hincal Evren , Batool Maryam , Asad Ullah Muhammad
Published: September 2024

In this study, we developed a fractional-order model for polycystic ovarian syndrome issue transmission in women through four compartments with the Mittag-Leffler kernel. For biological feasibility, we discussed the positivity and boundedness of solutions with fixed point mappings in Banach spaces. Sensitivity analysis is performed using different variables as response functions each time, employing Latin Hyper-cube Sampling (LHS) and Partial Rank Correlation Coefficient (PRCC) with 200 iterations. Further, the reproductive number is determined for the model’s biological feasibility with an analysis of parameter impact through Matlab software. The solutions are examined for global stability using the Lyapunov function with a first derivative. Chaos Control will use the regulate for linear responses approach to bring the system to stabilize according to its points of equilibrium. Numerical solutions are derived by using a Newton polynomial in the generalized form of the Mittag-Leffler kernel, which illustrates the effect of the fractional operator and parameters involved in the system. Results are also analyzed with different assumptions of parameter values and initial conditions to observe the different impacts of treatment to overcome the risk of infertility in women. Such type of investigation will be useful to investigate the spread of disease as well as helpful in developing control strategies to overcome the risk of problems and best management care pre-detection of the issue and for treatment.
Critical analysis of information provided by ChatGPT on lactate, exercise, fatigue, and muscle pain: current insights and future prospects for enhancement
Authors: Rocha-Silva Rizia , Rodrigues Mila Alves Matos , Viana Ricardo Borges , Nakamoto Fernanda Patti , Vancini Rodrigo Luiz , Andrade Marília Santos , Rosemann Thomas , Weiss Katja , Knechtle Beat , de Lira Claudio Andre Barbosa
Published: September 2024

Generative artificial intelligence (AI), exemplified by ChatGPT, provides immediate and easily accessible answers about lactate and exercise. However, the reliability of this information may fluctuate, contingent upon the scope and intricacy of the knowledge derived from the training process before most recent update. Furthermore, a deep understanding of the basic principles of human physiology becomes crucial for the effective correction and safe use of this technology.
Sex-based differences in the blood pressure responses to muscle metaboreflex activation are consistent between limb and respiratory muscle
Authors: Benbaruj Jenna M. , Leahy Michael G. , Jackman Rachel , Rae Thora , Boushel Robert , Foster Glen E. , Sheel A. William
Published: September 2024

With rhythmic handgrip exercise and inspiratory pressure threshold loading there was a time-dependent rise in the blood pressure that was significantly lower in females than males. The blunted blood pressure response in females was present whether handgrip or inspiratory workload was relative or absolute. An attenuated cardiovascular response to high levels of limb or respiratory muscle work may have implications for whole body exercise in health and disease.
Transvenous phrenic nerve stimulation reduces diaphragm injury during controlled mechanical ventilation in a preclinical model of ARDS
Authors: Rohrs Elizabeth C. , Fernandez Karl C. , Bassi Thiago G. , Nicholas Michelle , Wittmann Jessica , Ornowska Marlena , Gani Matt , Dakin Isabella , Reynolds Steven C.
Published: September 2024

This study adds to our understanding of applying transvenous diaphragm neurostimulation synchronously with mechanical ventilation by examining its effects on diaphragm muscle injury and cytokine concentration patterns in pigs with acute respiratory distress syndrome (ARDS). We observed that using this therapy for 12 h post lung injury mitigated ventilator-induced diaphragm injury and changed the pattern of cytokine concentration measured in diaphragm tissue. These findings suggest that transvenous diaphragm neurostimulation is an exciting tool for lung and diaphragm protective ventilation.
Sulforaphane Alleviates Bisphenol A‐Induced Glucose Intolerance via Improving Inflammation and Oxidative Stress
Authors: Hong Lixia , Xu Yide , Wang Dongdong , Zhang Qi , Li Xiaoting , Xie Chunfeng , Wu Jieshu , Zhong Caiyun , Gao Gu , Ding Ye , Geng Shanshan
Published: September 2024

Background. Bisphenol A (BPA) disrupts glucose homeostasis via inflammatory pathways in liver cells, affecting insulin sensitivity. This study examines sulforaphane (SFN), known for its anti‐inflammatory and antioxidative properties, for counteracting BPA’s effects. Methods. We evaluated SFN’s impact on BPA‐exposed C57/BL6J mice and HepG2 cells, focusing on metabolic parameters, insulin signaling, and inflammatory markers. Mice were treated with SFN (10 mg/kg) for six weeks, with assessments including body weight, serum glucose, insulin levels, and glucose tolerance. Molecular analyses in both models included gene expressions related to glucose metabolism, insulin and MAPK signaling pathways, and markers of inflammation and oxidative stress. Results. SFN reduced blood glucose and improved glucose tolerance of BPA‐treated mice. In BPA‐treated HepG2 cells, SFN significantly boosted glucose consumption in vitro. Moreover, SFN treatment enhanced the protein expression of phosphorylated‐insulin receptor and phosphorylated‐AKT and reversed glycolytic and gluconeogenic gene expression in HepG2 cells and mice liver. SFN also decreased phosphorylation levels of p38 and JNK and reduced inflammation and oxidative stress markers in vitro and in vivo. Conclusion. Our findings underscore SFN’s capacity to ameliorate BPA‐induced glucose intolerance and insulin resistance by enhancing hepatic insulin signaling and metabolic functions. This action is likely mediated through SFN’s inhibitory effects on inflammatory and oxidative pathways. Consequently, SFN holds promise as an intervention for mitigating BPA‐related metabolic disorders.
Effect of Starvation on the Serum Physiology, Transcriptome and Intestinal Microbiota of Juvenile Largemouth Bass (Micropterus salmoides)
Authors: Wang Huan , Zhou Huaxing , Jiang He , Hu Yuting , Li Tong , Duan Guoqing
Published: September 2024

Starvation is common in fish, particularly during the juvenile period, and is typically caused by environmental changes. However, the molecular mechanisms of juvenile Micropterus salmoides in response to starvation are still poorly understood. We elucidated changes in the serum physiology, transcriptome, and intestinal microbiome of M. salmoides after 14 days of starvation. Body weight and serum concentrations of glucose, cholesterol, triglycerides, and alkaline phosphatase significantly decreased during the starvation period. However, serum concentrations of aspartate transaminase and alanine transaminase were significantly elevated. Transcriptome analysis of liver tissues from commonly fed fish and starved fish revealed 1069 differentially expressed genes (DEGs), of which 211 were up‐regulated. In total, 586 DEGs were identified in the intestinal tissues, of which 166 were up‐regulated and 420 were down‐regulated. KEGG analysis revealed that starvation affected multiple pathways, particularly those related to energy, metabolism and immunity. Starvation limited fatty acid biosynthesis and elongation in the liver, down‐regulated immunity‐related genes in the intestine and promoted fatty acid degradation. The 16S rDNA analysis revealed that starvation altered intestinal microbiota homeostasis and increased intestinal Shannon diversity. Two opposite patterns of dominant genera emerged in commonly fed fish (most abundant genus is Mycoplasma) and in starved fish (most abundant genus is Cetobacterium). Starvation also increased the abundance of pathogens, including Plesiomonas and Aeromonas. Our study will provide the theoretical basis for assessing the starvation levels and nutritional status of juvenile fish and guidance for further studies on starvation in the context of fish physiology and health.
Targeting Fatty Acid Metabolism Abrogates the Differentiation Blockade in Preleukemic Cells
Authors: Liu Xiaoyu , Liu Yu , Rao Qing , Mei Yihan , Xing Haiyan , Gu Runxia , Mou Junli , Chen Manling , Ding Fan , Xie Wanqing , Tang Kejing , Tian Zheng , Wang Min , Qiu Shaowei , Wang Jianxiang
Published: September 2024

Metabolism plays a key role in the maintenance of normal hematopoietic stem cells (HSC) and in the development of leukemia. A better understanding of the metabolic characteristics and dependencies of preleukemic cells could help identify potential therapeutic targets to prevent leukemic transformation. As AML1–ETO, one of the most frequent fusion proteins in acute myeloid leukemia that is encoded by a RUNX1::RUNX1T1 fusion gene, is capable of generating preleukemic clones, in this study, we used a conditional Runx1::Runx1t1 knockin mouse model to evaluate preleukemic cell metabolism. AML1–ETO expression resulted in impaired hematopoietic reconstitution and increased self-renewal ability. Oxidative phosphorylation and glycolysis decreased significantly in these preleukemic cells accompanied by increased HSC quiescence and reduced cell cycling. Furthermore, HSCs expressing AML1–ETO exhibited an increased requirement for fatty acids through metabolic flux. Dietary lipid deprivation or loss of the fatty acid transporter FATP3 by targeted deletion using CRISPR/Cas9 partially restored differentiation. These findings reveal the unique metabolic profile of preleukemic cells and propose FATP3 as a potential target for disrupting leukemogenesis.

Significance: Fatty acid metabolism is required for maintenance of preleukemic cells but dispensable for normal hematopoiesis, indicating that dietary lipid deprivation or inhibiting fatty acid uptake may serve as potential strategies to prevent leukemogenesis.
Hepatocellular Carcinoma Immune Microenvironment Analysis: A Comprehensive Assessment with Computational and Classical Pathology
Authors: Ercan Caner , Renne Salvatore Lorenzo , Di Tommaso Luca , Ng Charlotte K.Y. , Piscuoglio Salvatore , Terracciano Luigi M.
Published: September 2024

Purpose:

The spatial variability and clinical relevance of the tumor immune microenvironment (TIME) are still poorly understood for hepatocellular carcinoma (HCC). In this study, we aim to develop a deep learning (DL)–based image analysis model for the spatial analysis of immune cell biomarkers and microscopically evaluate the distribution of immune infiltration.

Experimental Design:

Ninety-two HCC surgical liver resections and 51 matched needle biopsies were histologically classified according to their immunophenotypes: inflamed, immune-excluded, and immune-desert. To characterize the TIME on immunohistochemistry (IHC)-stained slides, we designed a multistage DL algorithm, IHC-TIME, to automatically detect immune cells and their localization in the TIME in tumor–stroma and center–border segments.

Results:

Two models were trained to detect and localize the immune cells on IHC-stained slides. The framework models (i.e., immune cell detection models and tumor–stroma segmentation) reached 98% and 91% accuracy, respectively. Patients with inflamed tumors showed better recurrence-free survival than those with immune-excluded or immune-desert tumors. Needle biopsies were found to be 75% accurate in representing the immunophenotypes of the main tumor. Finally, we developed an algorithm that defines immunophenotypes automatically based on the IHC-TIME analysis, achieving an accuracy of 80%.

Conclusions:

Our DL-based tool can accurately analyze and quantify immune cells on IHC-stained slides of HCC. Microscopic classification of the TIME can stratify HCC according to the patient prognosis. Needle biopsies can provide valuable insights for TIME-related prognostic prediction, albeit with specific constraints. The computational pathology tool provides a new way to study the HCC TIME.
TAK1 Promotes an Immunosuppressive Tumor Microenvironment through Cancer-Associated Fibroblast Phenotypic Conversion in Pancreatic Ductal Adenocarcinoma
Authors: Sheng Nan , Shindo Koji , Ohuchida Kenoki , Shinkawa Tomohiko , Zhang Bo , Feng Haimin , Yamamoto Takeo , Moriyama Taiki , Ikenaga Naoki , Nakata Kohei , Oda Yoshinao , Nakamura Masafumi
Published: September 2024

Purpose:

We aim to clarify the precise function of TGFβ1-activated kinase 1 (TAK1) in cancer-associated fibroblasts (CAF) within human pancreatic ductal adenocarcinoma (PDAC) by investigating its role in cytokine-mediated signaling pathways.

Experimental Design:

The expression of TAK1 in pancreatic cancer was confirmed by The Cancer Genome Atlas data and human pancreatic cancer specimens. CAFs from freshly resected PDAC specimens were cultured and used in a three-dimensional model for direct and indirect coculture with PDAC tumors to investigate TAK1 function. Additionally, organoids from [LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre (KPC)] mice were mixed with CAFs and injected subcutaneously into C57BL/6 mice to explore in vivo functional interactions of TAK1.

Results:

The Cancer Genome Atlas data revealed significant upregulation of TAK1 in PDAC, associating with a positive correlation with the T-cell exhaustion signature. Knockdown of TAK1 in CAFs decreased the inflammatory CAF signature and increased the myofibroblastic CAF signature both in vitro and in vivo. The absence of TAK1 hindered CAF proliferation, blocked several inflammatory factors via multiple pathways associated with immunosuppression, and hindered epithelial–mesenchymal transition and outgrowth in vitro in spheroid cocultures with PDAC cells. Additionally, TAK1 inhibitor restrained tumor growth, increased CD4+ and CD8+ T-cell abundance, and reduced immunosuppressive cells present in vivo.

Conclusions:

Blocking the TAK1+ CAF phenotype leads to the conversion of protumorigenic CAFs to antitumorigenic CAFs. This highlights TAK1 as a potential therapeutic target, particularly in CAFs, and represents a novel avenue for combined immunotherapy in PDAC.