bluuebunny/crossref_metadata_2025 huggingface dataset:
Improvements in advanced hepatocellular carcinoma to repeat implementation of primary protocol after cancer progression occurs following sequential systemic therapy and a clinical trial: A case report
Authors: Huang Hongwei , Wei Qiaoqiao , Leng Chao , Wang Hao , Mei Bin
Published: May 2024

Introduction:

Systemic therapy is recommended for patients with advanced hepatocellular carcinoma (aHCC). However, drug resistance occurs over time when patients receive systemic therapy, resulting in cancer progression. Due to the lack of relevant clinical trials, optimizing subsequent treatments after cancer progression remains elusive.

Patient concerns:

A 52-year-old male patient presented with epigastric discomfort and fatigue for almost 1 month with a past history of chronic hepatitis B virus infection for 30 years.

Diagnosis:

Based on the patient’s performance status, tumor status assessed by computed tomography, liver function, he was diagnosed with HCC at BCLC stage C.

Interventions and Outcomes:

He first received transarterial chemoembolization (TACE) combined with sintilimab and lenvatinib as first-line treatment and experienced 10-month progression-free survival. After cancer progression, the patient participated in a clinical trial of ABSK-011, a novel fibroblast growth factor receptor 4 inhibitor, with a frustrating result. Then, the patient underwent TACE and received sintilimab plus lenvatinib again. Surprisingly, the tumor had a partial response, and the patient’s serum alpha-fetoprotein returned to normal.

Lessons:

The combined treatment of TACE plus systemic therapy might be an appropriate subsequent treatment.
The concept of folic acid supplementation and its role in prevention of neural tube defect among pregnant women: PRISMA
Authors: Seyoum Tola Fikadu
Published: May 2024

Folic acid is the synthetic form of vitamin B9, found in supplements and fortified foods, while folate occurs naturally in foods. Folic acid and its derivatives are extremely important in the synthesis of nucleic acids (DNA and ribose nucleic acid [RNA]) and different proteins. It acts as a coenzyme for the transfer of 1 carbon in the biosynthesis of purine, pyrimidine, and amino acids. Folic acid is critically important in rapidly proliferating tissues, including fetus and trophoblastic tissue to prevent neural tube defect (NTD). The main objective of this review is to identify the role of folic acid to prevent NTD among pregnancy mothers. Electronic databases including Web of Science, Google Scholar, MEDLINE, Scopus, and Cochrane library used to systematically search without limitation of publication date and status. In pregnancy, the first trimester is a significant time for neural tube closure. Decreased blood folic acid levels inhibit DNA replication, repair, RNA synthesis, histone and DNA methylation, methionine production, and homocysteine remethylation reactions that cause NTDs in pregnancy. Therefore, folic acid supplementation is critically important for childbearing mothers before conception and in the first trimester pregnancy. As a result, women are recommended to take 400 microgram FA/day from preconception until the end of the first trimester to prevent NTD-affected pregnancies. This allows the developing neural tissue to acquire critical mass and provides the preferred rostrocaudal orientation so that these divisions contribute to the elongation of the developing neural tube in embryos.
Evaluation of thyroid congestion in patients with heart failure using shear wave elastography: An observational study
Authors: Sakamoto Takahiro , Asanuma Toshihiko , Uchida Kazuhiko , Kawahara Hiroshi , Endo Akihiro , Yoshitomi Hiroyuki , Tanabe Kazuaki
Published: May 2024

Shear wave elastography (SWE) is a noninvasive method for measuring organ stiffness. Liver stiffness measured using SWE reflects hepatic congestion in patients with heart failure (HF). However, little is known about the use of SWE to assess other organ congestions. This study aimed to evaluate the utility of SWE for assessing not only the liver but also thyroid congestion in patients with HF. This prospective study included 21 patients with HF who have normal thyroid lobes (age: 77.0 ± 11.0, men: 14). Thyroid and liver stiffness were measured by SWE using the ARIETTA 850 ultrasonography system (Fujifilm Ltd., Tokyo, Japan). SWE of the thyroid was performed on B-mode ultrasonography; a target region was identified within a region of interest. SWE was performed in each lobe of the thyroid gland. Five measurements were taken at the same location and the averages were recorded for comparison. We investigated the relationship between SWE for evaluating thyroid stiffness and the clinical characteristics of patients with HF. SWE of the thyroid was significantly correlated with SWE of the liver (R = 0.768, P < .001), thyroid stimulation hormone (R = 0.570, P = .011), free thyroxine (R = 0.493, P = .032), estimated right atrial pressure (RAP; R = 0.468, P = .033), and composite congestion score (R = 0.441, P = .045). SWE may be useful for evaluating thyroid stiffness and assessing the degree of thyroid congestion. Thyroid congestion may reflect the elevation of RAP and cause thyroid dysfunction through organ congestion.
Which is a real valuable screening tool for lung cancer and measure thoracic diseases, chest radiography or low-dose computed tomography?: A review on the current status of Japan and other countries
Authors: Kasuga Ikuma , Yokoe Yoshimi , Gamo Sanae , Sugiyama Tomoko , Tokura Michiyo , Noguchi Maiko , Okayama Mayumi , Nagakura Rei , Ohmori Nariko , Tsuchiya Takayoshi , Sofuni Atsushi , Itoi Takao , Ohtsubo Osamu
Published: May 2024

Chest radiography (CR) has been used as a screening tool for lung cancer and the use of low-dose computed tomography (LDCT) is not recommended in Japan. We need to reconsider whether CR really contributes to the early detection of lung cancer. In addition, we have not well discussed about other major thoracic disease detection by CR and LDCT compared with lung cancer despite of its high frequency. We review the usefulness of CR and LDCT as veridical screening tools for lung cancer and other thoracic diseases. In the case of lung cancer, many studies showed that LDCT has capability of early detection and improving outcomes compared with CR. Recent large randomized trial also supports former results. In the case of chronic obstructive pulmonary disease (COPD), LDCT contributes to early detection and leads to the implementation of smoking cessation treatments. In the case of pulmonary infections, LDCT can reveal tiny inflammatory changes that are not observed on CR, though many of these cases improve spontaneously. Therefore, LDCT screening for pulmonary infections may be less useful. CR screening is more suitable for the detection of pulmonary infections. In the case of cardiovascular disease (CVD), CR may be a better screening tool for detecting cardiomegaly, whereas LDCT may be a more useful tool for detecting vascular changes. Therefore, the current status of thoracic disease screening is that LDCT may be a better screening tool for detecting lung cancer, COPD, and vascular changes. CR may be a suitable screening tool for pulmonary infections and cardiomegaly.
The efficacy and safety of leucine-enriched essential amino acids in knee osteoarthritis patients: A randomized controlled trial
Authors: Park Seung-Jun , Nam Chang Hyun , Ahn Hye Sun , Kim Taehyun
Published: May 2024

Background:

Supplementation with leucine-enriched essential amino acids (LEAAs) has shown efficacy in the recovery of muscle injury and activation of muscle synthesis. Muscle function in knee osteoarthritis is a crucial factor for managing pain and preserving ambulatory function. However, the efficacy and safety of LEAAs supplementation in patients with knee osteoarthritis have not been evaluated.

Methods:

In this prospective analysis, we evaluated the efficacy and safety of supplementation with 12 g of LEAAs daily for 8 weeks in knee-symptomatic osteoarthritis patients. For assessing the efficacy, clinical pain, calf circumference, and disability were assessed using questionnaires (visual analog scale, Knee Society Score, and 36-item short form survey [SF-36]), laboratory analyses (total protein and albumin), and radiologic study (dual-energy X-ray absorptiometry [DEXA]) for muscle and bone density. To evaluate safety, generalized or localized protein allergic reactions, complete blood count, liver and kidney function, and serum glucose were measured.

Results:

Sixty-five participants, categorized into the experimental (n = 32) and control (n = 33) groups, were included in this 8-week trial from March 2022 to July 2022. A significantly higher efficacy was observed in the experimental group than in the control group, as indicated by muscle density in the DEXA scan (P = .001) and SF-36 (P < .001). The safety evaluation revealed no related generalized or local protein allergy. Hematological findings, serum glucose, and kidney and liver toxicity were not significantly different between the groups.

Conclusion:

Supplementation with leucine-enriched proteins is safe and efficacious in the improvement of muscle density and quality of life.
Logistic regression analysis of the value of biomarkers, clinical symptoms, and imaging examinations in COVID-19 for SARS-CoV-2 nucleic acid detection
Authors: Huang Sicheng , Zhang Xuebao , Ni Xihe , Chen Long , Ruan Feng
Published: May 2024

The detection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) nucleic acid detection provides a direct basis for diagnosing Coronavirus Disease 2019. However, nucleic acid test false-negative results are common in practice and may lead to missed diagnosis. Certain biomarkers, clinical symptoms, and imaging examinations are related to SARS-CoV-2 nucleic acid detection and potential predictors. We examined nucleic acid test results, biomarkers, clinical symptoms, and imaging examination data for 116 confirmed cases and asymptomatic infections in Zhuhai, China. Patients were divided into nucleic acid-positive and -false-negative groups. Predictive values of biomarkers, symptoms, and imaging for the nucleic acid-positive rate were calculated by Least Absolute Shrinkage and Selection Operators regression analysis and binary logistic regression analysis, and areas under the curve of these indicators were calculated. Hemoglobin (OR = 1.018, 95% CI: 1.006–1.030; P = .004) was higher in the respiratory tract-positive group than the nucleic acid-negative group, but platelets (OR = 0.996, 95% CI: 0.993–0.999; P = .021) and eosinophils (OR = 0.013, 95% CI: 0.001–0.253; P = .004) were lower; areas under the curve were 0.563, 0.614, and 0.642, respectively. Some biomarkers can predict SARS-CoV-2 viral nucleic acid detection rates in Coronavirus Disease 2019 and are potential auxiliary diagnostic tests.
Retrospective study of qualitative assessment in detecting synchronous and metachronous malignancies in adult cancer patients by 18F-FDG PET/CT
Authors: Lau Jeremy Hugh Yen-hey , Ng Koon Kiu , Wong Wai Chung , Ng Kwok Sing , Chu King Sun , Au-Yong Ting Kun , Kung Boom Ting
Published: May 2024

Objectives

The study aimed to evaluate the frequency of incidental suspicious lesions detected by flourine-18 fluorodeoxyglucose PET/computed tomography (18F-FDG PET/CT) scans done for staging or restaging in adult cancer patients. We further determined the detection rate of synchronous and metachronous malignancies in these suspicious lesions after further investigations.

Materials and methods

This retrospective analysis evaluated the consecutive patients with 18F-FDG PET/CT scans done in Queen Elizabeth Hospital (QEH), Hong Kong between July 2021 and June 2022. The adult cancer patients who underwent staging or restaging 8F-FDG PET/CT were included while the remaining were excluded. Patients’ demographics, primary cancer type, tumor markers, and pathological analyses for the incidental suspicious lesions were reviewed to establish the detection rate of synchronous and metachronous malignancies.

Results

A total of 2054 patients fulfilled inclusion criteria with age ranging from 18 to 93 years old. Out of the 2054 patients, 304 (14.8%) were found to have incidental suspicious lesions. Of these, 206 patients (67.8%) underwent further investigations including pathological analyses. Subsequently, 84 of these 206 patients (40.8%) had pathologically proven synchronous or metachronous malignancies.

Conclusion

The detection rate of incidental suspicious lesions in adult cancer patients who underwent 18F-FDG PET/CT scans for staging or restaging was 14.8% and the rate of synchronous and metachronous malignancies in these suspicious lesions was 40.8%. The treatment plan of these patients may potentially be altered, which should be included in the cost-benefit analysis of using this imaging modality.
A Novel Objective Pathologic Criterion for Isolated Hypoganglionosis
Authors: Tamaki Akihiko , Kohashi Kenichi , Yoshimaru Koichiro , Hino Yuko , Hamada Hiroshi , Kawakubo Naonori , Taguchi Tomoaki , Tajiri Tatsuro , Oda Yoshinao
Published: May 2024

Isolated hypoganglionosis (IHG) is histologically characterized by small numbers of myenteric ganglion cells and small myenteric ganglia; however, no numerical diagnostic criteria for IHG have been established. Therefore, this study aimed to develop quantitative pathologic criteria for IHG. We evaluated 160 resected intestinal tissue specimens from 29 pediatric autopsies and 10 IHG cases. These specimens were obtained from the jejunum, ileum, ascending colon, transverse colon, and rectum. Morphologic features of the myenteric ganglion cells and myenteric ganglia were quantified and analyzed in digitized HuC/HuD-immunostained and CD56-immunostained sections, respectively. Quantitative criteria were developed with a scoring system that used parameters with the area under the receiver operating characteristic curve (AUC) values >0.7 and sensitivity and specificity exceeding 70%. The selected parameters were the number of myenteric ganglion cells per cm and the number of myenteric ganglia with an area >2500 µm2per cm. The score for each parameter ranged from −1 to 2, and the total score of the scoring system ranged from −2 to 4. With a cutoff value of ≥2 (AUC, 0.98; 95% CI: 0.96-1.00), the scoring system had a sensitivity of 96% (95% CI: 0.82-1.00) and a specificity of 99% (95% CI: 0.95-1.00). We devised a novel pathologic criterion based on the quantification of the number of myenteric ganglion cells and ganglia. Furthermore, this criterion showed high diagnostic accuracy and could lead to a definitive diagnosis of IHG in clinical practice.
Human herpesvirus-6, HHV-8 and parvovirus B19 after allogeneic hematopoietic cell transplant: the lesser-known viral complications
Authors: Kampouri Eleftheria , Little Jessica S. , Crocchiolo Roberto , Hill Joshua A.
Published: May 2024

Purpose of review

Viral infections continue to burden allogeneic hematopoietic cell transplant (HCT) recipients. We review the epidemiology, diagnosis, and management of human herpesvirus (HHV)-6, HHV-8 and parvovirus B19 following HCT.

Recent findings

Advances in HCT practices significantly improved outcomes but impact viral epidemiology: post-transplant cyclophosphamide for graft-versus-host disease prevention increases HHV-6 reactivation risk while the impact of letermovir for CMV prophylaxis – and resulting decrease in broad-spectrum antivirals – is more complex. Beyond the well established HHV-6 encephalitis, recent evidence implicates HHV-6 in pneumonitis. Novel less toxic therapeutic approaches (brincidofovir, virus-specific T-cells) may enable preventive strategies in the future. HHV-8 is the causal agent of Kaposi's sarcoma, which is only sporadically reported after HCT, but other manifestations are possible and not well elucidated. Parvovirus B19 can cause severe disease post-HCT, frequently manifesting with anemia, but can also be easily overlooked due to lack of routine screening and ambiguity of manifestations.

Studies should establish the contemporary epidemiology of HHV-6, and other more insidious viruses, such as HHV-8 and parvovirus B19 following HCT and should encompass novel cellular therapies. Standardized and readily available diagnostic methods are key to elucidate epidemiology and optimize preventive and therapeutic strategies to mitigate the burden of infection.
Efficacy of Duloxetine With Arthrocentesis in the Management of TMJ Internal Derangement
Authors: Abdallah Asmaa Mousa Awadallah , El Fadly Mahmoud Abd El Aziz , Abdelfateh Sohib Mohamed Galal , Taha Moustafa Mohammed Sayed
Published: May 2024

Temporomandibular joint (TMJ) arthrocentesis is one of the most commonly used non-invasive surgical interventions in the treatment of refractory pain and dysfunction associated with internal derangement. Several adjunctive therapies have been used in combination with arthrocentesis in an attempt to increase its efficacy and long-term maintenance. Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor which is used in different chronic pain conditions. This study aimed to assess the efficacy of duloxetine in combination with arthrocentesis compared with arthrocentesis alone. Twenty-eight patients with chronic TMJ pain were included and randomly allocated into 2 groups (control and study groups). The control group included patients who underwent TMJ arthrocentesis only, and the study group included patients who underwent arthrocentesis followed by giving duloxetine (30 mg) orally twice daily for 3 months. Pain, maximum mouth opening, and level of anxiety and depression were assessed preoperatively and followed at regular intervals of 1 week, 1 month, 3 months, and 6 months postoperatively. Pain was significantly reduced in both groups at all postoperative intervals and was significantly lower in the study group than the control group at 6 months. Maximum mouth opening increased significantly in both groups, but the difference between them was not significant. Level of anxiety and depression was significantly decreased in both groups, with no statistically significant difference between them. The results of this study indicate that duloxetine in combination with arthrocentesis may provide effective and long-term pain control; however, its use is associated with a higher risk of adverse events.
Improving Environmental Sustainability of Operating Theatres
Authors: Lodhia Siya , Pegna Victoria , Abrams Ruth , Jackson Daniel , Rockall Timothy A. , Rizan Chantelle
Published: May 2024

Objective:

To understand views of staff in relation to attitudes, enablers, and barriers to implementation of environmentally sustainable surgery in operating theatres. This will ultimately help in the goal of successfully implementing more sustainable theatres.

Background:

Global health care sectors are responsible for 4.4% of greenhouse gas emissions. Surgical operating theatres are resource intensive areas and improvements will be important to meet Net-Zero carbon emissions within health care.

Methods:

Three databases were searched (Web of Science, Ovid, and PubMed), last checked January 2024. We included original manuscripts evaluating staff views regarding sustainable operating theatres. The Mixed Methods Appraisal Tool was used for quality appraisal and data analysed using thematic synthesis.

Results:

A total of 2933 articles were screened and 14 fulfilled inclusion criteria, using qualitative (1), quantitative (2), and mixed methods (11). Studies were undertaken in a variety of clinical (Department of Anaesthesia, Surgery, Otolaryngology, Obstetrics and Gynaecology and Ophthalmology) and geographical settings (Australia, Canada, France, Germany, New Zealand, United States, United Kingdom, and Ireland). Across studies there was a lack of evidence exploring enablers to implementation, but barriers mainly related to the following themes: education and awareness, leadership, resistance to change, facilities and equipment, time, and incentive.

Conclusions:

This systematic review identified attitudes and barriers perceived by clinicians towards improving environmental sustainability within operating theatres, which may inform future strategy towards sustainable surgery. Most studies used a survey-design, whereas use of interviews may provide deeper insights. Future work should be extended to wider stakeholders influencing operating theatres. In addition, implementation studies should be carried out to examine whether barriers do change in practice.
Comparison of Postoperative Outcomes Among Patients Treated by Male Versus Female Surgeons
Authors: Saka Natsumi , Yamamoto Norio , Watanabe Jun , Wallis Christopher , Jerath Angela , Someko Hidehiro , Hayashi Minoru , Kamijo Kyosuke , Ariie Takashi , Kuno Toshiki , Kato Hirotaka , Mohamud Hodan , Chang Ashton , Satkunasivam Raj , Tsugawa Yusuke
Published: May 2024

Objective:

To compare clinical outcomes of patients treated by female surgeons versus those treated by male surgeons.

Background:

It remains unclear as to whether surgical performance and outcomes differ between female and male surgeons.

Methods:

We conducted a meta-analysis to compare patients’ clinical outcomes—including patients’ postoperative mortality, readmission, and complication rates—between female versus male surgeons. MEDLINE, Embase, CENTRAL, ICTRP, and ClinicalTrials.gov were searched from inception to September 8, 2022. The update search was conducted on July 19, 2023. We used random-effects models to synthesize data and GRADE to evaluate the certainty.

Results:

A total of 15 retrospective cohort studies provided data on 5,448,121 participants. We found that patients treated by female surgeons experienced a lower postoperative mortality compared with patients treated by male surgeons [8 studies; adjusted odds ratio (aOR), 0.93; 95% CI, 0.88–0.97; I
2=27%; moderate certainty of the evidence]. We found a similar pattern for both elective and nonelective (emergent or urgent) surgeries, although the difference was larger for elective surgeries (test for subgroup difference P=0.003). We found no evidence that female and male surgeons differed for patient readmission (3 studies; aOR, 1.20; 95% CI, 0.83–1.74; I
2=92%; very low certainty of the evidence) or complication rates (8 studies; aOR, 0.94; 95% CI, 0.88–1.01; I
2=38%; very low certainty of the evidence).

Conclusion:

This systematic review and meta-analysis suggests that patients treated by female surgeons have a lower mortality compared with those treated by male surgeons.
Gas6/AXL Alleviates Hepatic Ischemia/Reperfusion Injury by Inhibiting Ferroptosis via the PI3K/AKT Pathway
Authors: Zhan Mengting , Liu Deng , Yao Lei , Wang Weizhi , Zhang Ruixin , Xu Yaru , Wang Zhen , Yan Qi , Fang Qi , Du Jian , Chen Lijian
Published: May 2024

Background.

Hepatic ischemia/reperfusion (I/R) injury is a major cause of complications in clinical liver surgery. AXL receptor tyrosine kinase (AXL) is a member of the TAM receptor tyrosine kinase family (TYRO3, AXL, and MERTK). Our previous study has shown that AXL expression was markedly upregulated in liver transplantation patients. However, the underlying mechanism of AXL in hepatic I/R injury remains unclear.

Methods.

A mouse liver warm I/R model and a primary hepatocyte hypoxia/reoxygenation model were established to investigate the role of AXL activation and ferroptosis in hepatic I/R injury by pretreating with recombinant mouse growth arrest-specific protein 6 (AXL activator) or R428 (AXL inhibitor). Moreover, we used LY294002 (phosphatidylinositol 3-kinase [PI3K] inhibitor) to evaluate the relationship between the PI3K/AKT (the Ser and Thr kinase AKT) pathway and ferroptosis in hepatic I/R injury.

Results.

Hepatic I/R injury decreased phosphorylation AXL expression and enhanced ferroptosis in liver transplantation patients and hepatic I/R-subjected mice. AXL activation attenuated lipid peroxidation and ferroptosis in hepatic I/R injury in vivo and in vitro. Inhibition of AXL activation exacerbated liver pathological damage and liver dysfunction, as well as iron accumulation and lipid peroxidation in hepatic I/R injury. Mechanistically, activated growth arrest-specific protein 6/AXL and its downstream PI3K/AKT signaling pathway inhibited ferroptosis during hepatic I/R injury.

Conclusions.

AXL activation protects against hepatic I/R injury by preventing ferroptosis through the PI3K/AKT pathway. This study is the first investigation on the AXL receptor and ferroptosis, and activating AXL to mitigate ferroptosis may be an innovative therapeutic strategy to combat hepatic I/R injury.
What is needed for the roll-out of psychedelic treatments?
Authors: Xenakis Stephen N. , Shannon Scott M.
Published: May 2024

Purpose of review

The pace of psychedelic treatments continues to increase. Regulation and coherent clinical guidance have not been established. A philosophical divide limits effective resolution of a practice delivery quandary: is this primarily a pharmacological or psychotherapeutic intervention?

Recent findings

Lykos (formerly MAPS) has submitted its new drug application (NDA) request to the FDA for 3-4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for PTSD and is expecting a response by the summer of 2024. Australia endorsed psilocybin and MDMA for regulated use in 2023. Multiple phase II and III clinical trials are also being conducted in the United States and Europe to study the use of psilocybin. Currently, Colorado and Oregon have legalized psilocybin in different manners. In Colorado, plants containing psilocybin, ibogaine, dimethyltryptamine (DMT) and mescaline (other than peyote) are now legal to possess, share and cultivate. Guidelines for regulated treatment with psilocybin containing mushrooms are in process with service delivery to begin early in 2025. In Oregon, clients must complete a preparation session with a licensed facilitator before consuming psilocybin products at a licensed service center. A prescription is not required. It is expected that other states will follow suit with a ballot measure likely in Massachusetts this year. Additionally, in the United States, the DEA, state boards, pharmaceutical distributors, and professional liability carriers all share mounting concerns about the in-home use of compounded ketamine used as a psychedelic therapeutic via remote prescribing.

Psychedelic treatments are rapidly entering the mainstream of medical care delivery in the United States. Clinical guidelines are urgently needed to ensure well tolerated practice and coherent regulation. The delivery of this guidance is limited by a core philosophical disagreement. Resolution of this conflict will be needed to deliver coherent clinical guidelines. Current research and clinical experience provide a solid foundation for practical clinical guidance and the introduction of psychedelics into healthcare.
Genomic diversity of novel strains of mammalian gut microbiome derived Clostridium XIVa strains is driven by mobile genetic element acquisition
Authors: Kamat Maya , Ormsby Michael J. , Humphrey Suzanne , Dixit Shivendra K , Thummler Katja , Lapsley Craig , Crouch Kathryn , Jukes Caitlin , Hulme Heather , Burchmore Richard , Meikle Lynsey , Pritchard Leighton , Wall Daniel M
Published: May 2024

Despite advances in sequencing technologies that enable a greater understanding of mammalian gut microbiome composition, our ability to determine a role for individual strains is hampered by our inability to isolate, culture and study such microbes. Here we describe highly unusual Clostridium XIVa group strains isolated from the murine gut. Genome sequencing indicates that these strains, Clostridium symbiosum LM19B and LM19R and Clostridium clostridioforme LM41 and LM42, have significantly larger genomes than most closely related strains. Genomic evidence indicates that the isolated LM41 and LM42 strains diverge from most other Clostridium XIVa strains and supports reassignment of these groups at genus-level. We attribute increased C. clostridioforme LM41 and LM42 genome size to acquisition of mobile genetic elements including dozens of prophages, integrative elements, putative group II introns and numerous transposons including 29 identical copies of the IS66 transposase, and a very large 192 Kb plasmid. antiSmash analysis determines a greater number of biosynthetic gene clusters within LM41 and LM42 than in related strains, encoding a diverse array of potential novel antimicrobial compounds. Together these strains highlight the potential untapped microbial diversity that remains to be discovered within the gut microbiome and indicate that, despite our ability to get a top down view of microbial diversity, we remain significantly blinded to microbe capabilities at the strain level.
Sinomonas terricola sp. nov., a plant-beneficial bacterium isolated from litchi rhizosphere soil in Guangdong, China
Authors: Wan Jiaxin , Zhou Yang , Sun Hui , Li Huaping , Yao Qing , Zhu Honghui
Published: May 2024

A novel plant-beneficial bacterium strain, designated as JGH33T, which inhibited Peronophythora litchii sporangia germination, was isolated on Reasoner's 2A medium from a litchi rhizosphere soil sample collected in Gaozhou City, Guangdong Province, PR China. Cells of strain JGH33T were Gram-stain-positive, aerobic, non-motile, bent rods. The strain grew optimally at 30–37 °C and pH 6.0–8.0. Sequence similarity analysis based on 16S rRNA genes indicated that strain JGH33T exhibited highest sequence similarity to Sinomonas albida LC13T (99.2 %). The genomic DNA G+C content of the isolate was 69.1 mol%. The genome of JGH33T was 4.7 Mbp in size with the average nucleotide identity value of 83.45 % to the most related reference strains, which is lower than the species delineation threshold of 95 %. The digital DNA–DNA hybridization of the isolate resulted in a relatedness value of 24.9 % with its closest neighbour. The predominant respiratory quinone of JGH33T was MK-9(H2). The major fatty acids were C15 : 0 anteiso (43.4 %), C16 : 0 iso (19.1 %) and C17 : 0 anteiso (19.3 %), and the featured component was C18 : 3 ω6c (1.01 %). The polar lipid composition of strain JGH33T included diphosphatidylglycerol, phosphatidylglycerol, dimannosylglyceride, phosphatidylinositol and glycolipids. On the basis of polyphasic taxonomy analyses data, strain JGH33T represents a novel species of the genus Sinomonas, for which the name Sinomonas terricola sp. nov. is proposed, with JGH33T (=JCM 35868T=GDMCC 1.3730T) as the type strain.
Anatomics MLT, an AI tool for large scale quantification of ultrastructural traits
Authors: Brookhouse Aaron , Ji Yuting , Knoblauch Jan , Gaburak Petr , Wager Brittney M. , Lin Zudi , Kunz Hans-Henning , Gebremedhin Assefaw H. , Pfister Hanspeter , Peters Winfried S. , Wei Donglai , Knoblauch Michael
Published: May 2024

The ever increasing breadth of biological knowledge has led to recent efforts to combine information from various fields into cell– or tissue atlases. Anatomical features are the structural basis for such efforts, but unfortunately large scale analysis of subcellular anatomical traits is currently a missing feature. Similarly, small phenotypic alterations of organelle– or cell-specific anatomical traits, such as an increase of the total volume or the number of mitochondria in response to certain stimuli, are currently hard to quantify. To provide tools to extract quantitative information from available 3D microscopic datasets generated with methods such as serial block face scanning electron microscopy we a) developed much improved fixation and embedding protocols for plants to drastically reduce processing artifacts and b) generated an easy-to-use AI tool for quantitative analysis and visualization of large-scale data sets. We make this tool available as open source.
AmpliconSuite: an end-to-end workflow for analyzing focal amplifications in cancer genomes
Authors: Luebeck Jens , Huang Edwin , Kim Forrest , Liefeld Ted , Dameracharla Bhargavi , Ahuja Rohil , Schreyer Daniel , Prasad Gino , Adamaszek Michał , Kenkre Rishaan , Agashe Tushar , Torvi Devika , Tabor Thorin , Giurgiu Mădălina , Kim Soyeon , Kim Hoon , Bailey Peter , Verhaak Roel G.W. , Deshpande Viraj , Reich Michael , Mischel Paul S. , Mesirov Jill , Bafna Vineet
Published: May 2024

Focal amplifications in the cancer genome, particularly extrachromosomal DNA (ecDNA) amplifications, are emerging as a pivotal event in cancer progression across diverse cancer contexts, presenting a paradigm shift in our understanding of tumor dynamics. Simultaneously, identification of the various modes of focal amplifications is bioinformatically challenging. We present AmpliconSuite, a collection of tools that enables robust identification of focal amplifications from whole-genome sequencing data. AmpliconSuite includes AmpliconSuite- pipeline; utilizing the AmpliconArchitect (AA) method, and AmpliconRepository.org; a community- editable website for the sharing of focal amplification calls. We also describe improvements made to AA since its initial release that improve its accuracy and speed. As a proof of principle, we utilized publicly available pan-cancer datasets encompassing 2,525 tumor samples hosted onAmpliconRepository.orgto illustrate important properties of focal amplifications, showing ecDNA has higher copy number, and stronger oncogene enrichment, compared to other classes of focal amplifications. Finally, we illustrate how AmpliconSuite-pipeline enables delineation of the various mechanisms by which ecDNA forms.
KRas, in addition to Tp53 is a driver for early carcinogenesis and a molecular target in a mouse model of invasive gastro-esophageal adenocarcinoma
Authors: Anand Akanksha , Schömig Linus , Lange Sebastian , Tran Li , Flisikowski Krzysztof , Öllinger Rupert , Rad Roland , Vieth Michael , Steiger Katja , Baumeister Theresa , Strangmann Julia , Algül Hana , Ciecielski Katrin , Böttcher Katrin , Fang Hsin-Yu , Carvalho Marcos Jόse Braz , Mohammad-Shahi Donja Sina , Gerland Sophie , Proaño-Vasco Andrea , Schnieke Angelika , Thimme Robert , Schmid Roland M. , Wang Timothy C. , Quante Michael
Published: May 2024

Objective

The incidence of gastro-esophageal adenocarcinoma (GEAC) has increased dramatically and is associated with Barrett’s Esophagus (BE). Gastric cardia progenitors are the likely origin for BE and GEAC. Here we analyzep53, Rb1andKrasalterations in Lgr5 progenitor cells during carcinogenesis.

Design

We introduced single and combined genetic alterations (p53, Rb1andKras) in Lgr5-expressing progenitor cells at the inflamed gastroesophageal junction in the L2-IL1b (L2) mouse model crossed toLgr5-CreERTmice. Forin-vitrotreatment we utilized mouse and human 3D organoids.

Results

Inactivation ofTp53orRb1alone (L2-LP and L2-LR mice) resulted in metaplasia, and mild dysplasia, while expression ofKrasG12D(L2-LK) accelerated dysplasia in L2-IL1b mice. Dual induction of genetic alteration in L2-LPR, L2-LKP and L2-LKR mice confirmed the accelerating role of mutantKras, with the development of invasive cancer in mice with combinedTp53andKrasalteration. All three genetic events in cardia progenitor cells generated invasive cancer at 6 months of age, with chromosomal instability (CNV). The dominant role ofKrasprompted us to treat with a SHP2 inhibitor in combination with an ERK or MEK inhibitor, leading to reduced growth inKrasmutant organoids. SHP2 and MEK inhibitionin-vivoreducedKrasdependent tumor formation.

Conclusion

In the first invasive GEAC mouse model,Krasmutation in combination with loss of tumor suppressor genes Tp53 or Rb1 emerges as a key player in GEAC and with importance of p53 and Rb1 in promoting metaplasia. Targeting this SHP2/MEK/KRAS pathway represents a promising therapeutic option forKrasaltered GEAC.

What is already known on this topic

The increased incidence of GEAC is challenging current screening and surveillance strategies. Therapeutic and preventive options are limited due to a lack of knowledge on the role of genetic alterations commonly associated with GEAC and their function during progression to dysplasia.

What this study adds

We generate the first invasive GEAC model and show thatKRASat least in combination with a second genetic alterations (Tp53 and/or Rb1) may be a driver of tumorigenesis, and targeting KRAS alterations could be a promising now treatment substitution.

How this study might affect research, practice or policy

Targeting KRAS alterations will be important for GEAC, especially as specific KRAS inhibitor are on the horizon. In addition, a concept of single genetic alteration inducing metaplasia as an adaptation to chronic inflammation might emerge as an important factor for surveillance.
Myosin ATPase inhibition fails to rescue the metabolically dysregulated proteome of nebulin-deficient muscle
Authors: Laitila Jenni , Seaborne Robert A.E. , Ranu Natasha , Kolb Justin S. , Wallgren-Pettersson Carina , Witting Nanna , Vissing John , Vilchez Juan Jesus , Zanoteli Edmar , Palmio Johanna , Huovinen Sanna , Granzier Henk , Ochala Julien
Published: May 2024

Nemaline myopathy (NM) is a genetic muscle disease, primarily caused by mutations in theNEBgene (NEB-NM) and with muscle myosin dysfunction as a major molecular pathogenic mechanism. Recently, we have observed that the myosin biochemical super-relaxed state was significantly impaired inNEB-NM, inducing an aberrant increase in ATP consumption and remodelling of the energy proteome in diseased muscle fibres. As the small-molecule Mavacamten is known to promote the myosin super-relaxed state and reduce the ATP demand, here, we tested its potency in the context ofNEB-NM. We first conductedin vitroexperiments in isolated single myofibres from patients and found that Mavacamten successfully reversed the myosin ATP over-consumption. Following this, we assessed its short-termin vivoeffects by using the conditional nebulin knock-out (cNebKO) mouse model and by subsequently performing global proteomics profiling in dissected soleus myofibres. After a four-week treatment period, we observed a remodelling of a large number of proteins in both cNebKO mice and their wild-type siblings. Nevertheless, these changes were not related to the energy proteome, indicating that short-term Mavacamten treatment is not sufficient to properly counterbalance the metabolically dysregulated proteome of cNebKO mice. Taken together, our findings emphasize Mavacamten potencyin vitrobut challenge its short-term efficacyin vivo.

Key points summary

No cure exists for nemaline myopathy, a type of genetic skeletal muscle disease mainly derived from mutations in genes encoding myofilament proteins.

Applying Mavacamten, a small molecule directly targeting the myofilament, to isolated membrane-permeabilized muscle fibres from human patients restored myosin energetic disturbances.

Treating a mouse model of nemaline myopathyin vivowith Mavacamten for four weeks, remodeled the skeletal muscle fibre proteome without any noticeable effects on energetic proteins.

Short-term Mavacamten treatment may not be sufficient to reverse the muscle phenotype in nemaline myopathy.
Assembly of a segrosome by a CTP-independent ParB-like protein
Authors: Sukhoverkov Kirill V. , Balaguer-Perez Francisco , Aicart-Ramos Clara , Maqbool Abbas , Chandra Govind , Moreno-Herrero Fernando , Le Tung B. K.
Published: May 2024

The ATP– and CTP-dependent ParA-ParB-parSsegrosome is a macromolecular complex that segregates chromosomes/plasmids in most bacterial species. CTP binding and hydrolysis enable ParB to slide on DNA and to bridge and condense DNA, thereby dictating the size and dynamics of the tripartite ParABScomplex. Several other evolutionarily distinct systems can also segregate DNA, although the full diversity of bacterial DNA partition systems is not yet known. Here, we identify a CTP-independent ParABSsystem that maintains a conjugative plasmid SCP2 in the filamentous bacteriumStreptomyces coelicolor. We demonstrate that an SCP2 ParB-like protein, ParT, loads onto DNA at an 18-bpparSsite and diffuses away to the adjacent DNA despite lacking an apparent CTPase domain and detectable NTPase activity. We further show thatparSDNA stimulates ParT transition from loading to a diffusing state to accumulate on DNA, and ParT activates the ATPase activity of its cognate partner protein ParA. We also identify numerous structural homologs of ParT, suggesting that CTP-independent diffusion on DNA might be widespread in bacteria despite being previously unappreciated. Overall, our findings uncover a CTP-independent DNA translocation as an alternative and unanticipated mechanism for the assembly of a bacterial DNA segregation complex and suggest that CTP binding and hydrolysis is not a fundamental feature of ParABS-like systems.
Evolution towards extremely high β-lactam resistance inMycobacterium abscessusoutbreak strains
Authors: le Run Eva , Tettelin Hervé , Holland Steven M. , Zelazny Adrian M.
Published: May 2024

Treatment ofMycobacterium abscessuspulmonary disease requires multiple antibiotics including intravenous β-lactams (e.g., imipenem, meropenem).M. abscessusproduces a β-lactamase (BlaMab) that inactivates β-lactam drugs but less efficiently carbapenems. Due to intrinsic and acquired resistance inM. abscessusand poor clinical outcomes, it is critical to understand the development of antibiotic resistance both within the host and in the setting of outbreaks.

We compared serial longitudinally collectedM. abscessussubsp.massilienseisolates from the index case of a CF center outbreak and four outbreak-related strains. We found strikingly high imipenem resistance in the later patient isolates, including the outbreak strain (MIC >512 µg/ml). The phenomenon was recapitulated upon exposure of intracellular bacteria to imipenem. Addition of the β-lactamase inhibitor avibactam abrogated the resistant phenotype. Imipenem resistance was caused by an increase in β-lactamase activity and increasedblaMabmRNA level. Concurrent increase in transcription of precedingppiAgene indicated upregulation of the entire operon in the resistant strains.

Deletion of the porinmspAcoincided with the first increase in MIC (from 8 to 32 µg/ml). A frameshift mutation inmsp2responsible for the rough colony morphology, and a SNP in ATP-dependent helicasehrpAco-occurred with the second increase in MIC (from 32 to 256 µg/ml). Increased BlaMabexpression and enzymatic activity may have been due to altered regulation of theppiA-blaMaboperon by the mutated HrpA alone, or in combination with other genes described above. This work supports using carbapenem/β-lactamase inhibitor combinations for treatingM. abscessus, particularly imipenem resistant strains.
Impact of the COVID-19 pandemic on antidiabetic drugs initiation in Sweden, an interrupted time series study
Authors: Khanyk Nataliia , Nyberg Fredrik , Wettermark Björn , Li Huiqi , Eeg-Olofsson Katarina , Gudbjornsdottir Soffia , Hajiebrahimi Mohammadhossein
Published: May 2024

Aim

To investigate the impact of the COVID-19-pandemic on antidiabetic drug initiation

Methods

Using Swedish national health registers, an interrupted time series study for all first-time dispensed antidiabetic drugs was performed. A minimum 14-month washout period was used. We calculated monthly cumulative incidence of antidiabetic drug initiations per 1000 population and estimated trends before and after the onset of the pandemic using segmented regression analysis.

Results

Among 167,889 participants between 1Mar2019 and 30Nov2021, male sex (53%), age 18-64 (55.3%), unmarried status (52.5%), upper secondary education level (46.2%), and being employed (53.5%) were the most frequent characteristics. Mar2020, there was an immediate level drop in antidiabetic drug initiation (β2=-0.087%, P=0.01); however, the trend exhibited a rapid increase thereafter. Significant immediate level drops were identified for DPP4i (−0.087%, P=0.01), GLP1a (−0.008%, P=0.01) and SGLT2i (−0.033%, P=0.003). Older people (≥65) showed the largest immediate drop for antidiabetic drug initiation (−0.272%, P=0.003). SGLT2i demonstrated an increasing pattern both before and after the pandemic while metformin did reveal an increasing pattern among patients ≥65 years old after the pandemic.

Conclusion

The results identified an immediate level drop at the onset of the pandemic for any antidiabetic drug initiation, but the trend increased rapidly thereafter.
Endovascular thrombectomy: an effective and safe therapy for perioperative ischemic stroke
Authors: Wang Feng , Xu Xiaoping , Zheng Ling , Zhong Jiawei , Wang En , Liu Yang , Ke Shaofa
Published: May 2024

Background

Perioperative ischemic stroke is a rare but devastating complication. Mechanical thrombectomy is a promising therapeutic method, but very little data is available on its efficacy and safety. This study aims to answer this question by comparing the clinical outcomes of perioperative and community-onset stroke patients after endovascular therapy.

Methods

A retrospective cohort study was conducted on a total of 35 perioperative and 584 community-onset acute ischemic stroke patients who underwent endovascular thrombectomy at our hospital over the past 3.5 years. The recanalization rate, clinical recovery and cerebral hemorrhage within 90 days after therapy were compared between these two patient groups.

Results

Endovascular thrombectomy provided perioperative and community-onset ischemic stroke patients with comparable rates of successful reperfusion (mTICI ≥ 2b grade) (97.1% vs. 97.3%;P= 0. 967) and favorable functional recovery (mRS ≤ 2) (51.4% vs. 43.3%,P= 0.348), with no increase in severe intracranial hemorrhage (0% vs. 2.6% and 1.0%, for hematoma ≥ 30% of infarcted tissue and intraventricular hemorrhage, respectively) within 90 days. In addition, perioperative stroke patients had higher prevalence of atrial fibrillation (42.9 % vs. 26.7 %;P= 0.038) and intracranial cerebral artery stenosis without clear embolism (17.1 % vs. 3.8 %;P< 0.001) than community-onset stroke patients.

Conclusions

Endovascular thrombectomy is an effective and safe therapeutic approach for patients with perioperative ischemic stroke, although the results need to be validated by further studies with larger populations. Atrial fibrillation and large artery stenosis may contribute to the pathogenesis of perioperative ischemic stroke.
Phylogeny of neocortical-hippocampal projections provides insight in the nature of human memory
Authors: Reznik Daniel , Majka Piotr , Rosa Marcello G P , Witter Menno P , Doeller Christian F
Published: May 2024

Throughout mammalian evolution, the hippocampal region, unlike the neocortex, largely preserved its cytoarchitectural organization and its role in mnemonic functions. This contrast raises the possibility that the hippocampal region receives different types of cortical input across species, which may be reflected in species-specific memory-related differences. To test this hypothesis, we examined differences in unimodal and transmodal cortical input to the hippocampal region in the rat, marmoset, macaque and human. Our results demonstrate that unlike unimodal cortical input, transmodal cortical input to the hippocampal region was selectively preserved during mammalian evolution. These findings suggest that memory-related processes in different species likely operate on different types of sensory information. Our observations provide a comparative anatomical framework elucidating the process of dimensionality reduction underlying the formation of human memory.