bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and efficacy of long-term sodium channel blocker therapy for early rhythm control: the EAST-AFNET 4 trial
Authors: Rillig Andreas , Eckardt Lars , Borof Katrin , Camm A John , Crijns Harry J G M , Goette Andreas , Breithardt Günter , Lemoine Marc D , Metzner Andreas , Rottner Laura , Schotten Ulrich , Vettorazzi Eik , Wegscheider Karl , Zapf Antonia , Heidbuchel Hein , Willems Stephan , Fabritz Larissa , Schnabel Renate B , Magnussen Christina , Kirchhof Paulus
Published: May 2024

Aims

Clinical concerns exist about the potential proarrhythmic effects of the sodium channel blockers (SCBs) flecainide and propafenone in patients with cardiovascular disease. Sodium channel blockers were used to deliver early rhythm control (ERC) therapy in EAST-AFNET 4.

Methods and results

We analysed the primary safety outcome (death, stroke, or serious adverse events related to rhythm control therapy) and primary efficacy outcome (cardiovascular death, stroke, and hospitalization for worsening of heart failure (HF) or acute coronary syndrome) during SCB intake for patients with ERC (n = 1395) in EAST-AFNET 4. The protocol discouraged flecainide and propafenone in patients with reduced left ventricular ejection fraction and suggested stopping therapy upon QRS prolongation >25% on therapy. Flecainide or propafenone was given to 689 patients [age 69 (8) years; CHA2DS2-VASc 3.2 (1); 177 with HF; 41 with prior myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention; 26 with left ventricular hypertrophy >15 mm; median therapy duration 1153 [237, 1828] days]. The primary efficacy outcome occurred less often in patients treated with SCB [3/100 (99/3316) patient-years] than in patients who never received SCB [SCBnever 4.9/100 (150/3083) patient-years, P < 0.001]. There were numerically fewer primary safety outcomes in patients receiving SCB [2.9/100 (96/3359) patient-years] than in SCBnever patients [4.2/100 (135/3220) patient-years, adjusted P = 0.015]. Sinus rhythm at 2 years was similar between groups [SCB 537/610 (88); SCBnever 472/579 (82)].

Conclusion

Long-term therapy with flecainide or propafenone appeared to be safe in the EAST-AFNET 4 trial to deliver effective ERC therapy, including in selected patients with stable cardiovascular disease such as coronary artery disease and stable HF.

Clinical Trial Registration ISRCTN04708680, NCT01288352, EudraCT2010-021258-20, www.easttrial.org
Interprofessional follow-up of patients with cancer in France (the SINPATIC study): a preliminary, qualitative study of the patient’s perspective
Authors: Mirat William , Moscova Laura , Lustman Matthieu , Dawidowicz Sebastien , Picot Genevieve , Lebel Audrey , Cittée Jacques , Ferrat Emilie
Published: May 2024

Background

In 2020, 19.2 million people were diagnosed with cancer, and nearly 10 million cancer patients died worldwide. An effective cancer care pathway must be based on coordination, multidisciplinarity, a personalized approach, and collaboration between stakeholders. Follow-up can be improved by good collaboration and communication between GPs and the cancer care team at a common level of organization.

Objectives

To study patients with solid cancers and assess their perceptions of the care pathway, the roles of the healthcare professionals involved, and interprofessional collaboration.

Methods

In a preliminary, qualitative study (part of the SINPATIC study of general practitioners, oncologists, nurses, and patients), adult patients with cancer in the Paris area of France were interviewed between January and April 2018. Using purposive sampling, 10 patients were recruited from hospital departments and primary care. An interview guide explored 3 themes: the care pathway, the stakeholders’ roles in follow-up, and interprofessional collaboration.

Results

For patients, dealing with cancer is a complex process of awareness, care provision, decision-making, task assignment, a lack of clarification of professional roles, a piecemeal announcement of the diagnosis of cancer by several stakeholders, organizational and administrative difficulties, non-formal collaboration in inertia (tending towards collaboration under construction), and with cancer follow-up that was usually parallel, sometimes shared, rarely sequential.

Conclusion

This SINPATIC substudy provided us a better understanding of the complexity of the patient care pathway. Looking forward, the present findings might stimulate thoughts on the design and development of interventional studies.
Need to Revise Classification of Physical Activity Intensity in Older Adults? The Use of Estimated METs, Measured METs, and V̇O2 Reserve
Authors: Skjødt Mathias , Tully Mark A , Tsai Li-Tang , Gejl Kasper Degn , Ørtenblad Niels , Jensen Kurt , Koster Annemarie , Visser Marjolein , Andersen Marianne Skovsager , Caserotti Paolo
Published: May 2024

Background

Multiples of resting metabolic rate (RMR) are often used to classify physical activity intensity, a concept known as the metabolic equivalent of task (MET). However, the METs metrics may misclassify physical activity intensity in older adults because of age-related changes in RMR and maximal aerobic capacity (V˙O2max). This study aimed to (i) compare classifications of activity intensity by estimated (METsestimated) and measured (METsmeasured) METs and (ii) compare physical activity classified by absolute (METsmeasured) versus relative intensity (%V˙O2Reserve) in older adults.

Methods

Ninety-eight adults aged 75–90 years participated in the study. RMR and V˙O2 during sitting, standing, daily activities, and 6-minute walking test were measured. V˙O2Reserve was defined as the difference between V˙O2max and RMR. Moderate and vigorous intensity was classified as 3 and 6 METs and 40% and 60% of V˙O2Reserve, respectively. Paired t tests and a confusion matrix were used to investigate aims 1 and 2, respectively.

Results

METsmeasured was 24% lower than the standard 1 MET of 3.5 mL O2·min−1·kg−1. METsestimated underestimated the intensity during daily and walking activities when compared to METsmeasured. Nevertheless, when comparing METsmeasured to percentages of V˙O2Reserve, a mismatch was shown for moderate intensity in 47%–67% of the participants during daily activities and 21% of the participants during self-selected gait speed.

Conclusions

Applying METsestimated for older adults leads to potential underestimation of physical activity intensity, suggesting that current classification metrics should be revised for older adults. V˙O2Reserve is a candidate metric for establishing precise physical activity intensity cut points for older adults.

Clinical Trials Registration Number: NCT04821713
Numerical modelling of earthquake sequences involving valving and pumping of fluids
Authors: Marguin Valentin , Simpson Guy
Published: May 2024

Faults in the upper crust are sometimes thought to act as self-sealing valves, episodically releasing highly overpressured fluids trapped at greater depth during earthquakes. They are also often considered to be capable of actively pumping fluids into or out of faults in response to coseismic volumetric strain, thermal pressurization or other mechanisms. In this study, we investigate how these different types of behaviour (i.e. valve versus pump) are manifested in earthquakes. We do this using a 2-D plane strain model where frictional sliding on a thrust fault that is fed by a fluid source at its base is coupled to porous flow, thermal pressurization and strong variations in permeability. Our results show that thermal pressurization leads to dramatic dynamic weakening that produces earthquakes that propagate as slip pulses producing large stress drop, large slip and high slip velocities. On the other hand, valve-type behaviour typically produces smaller, less energetic earthquakes that commonly arrest before rupturing the entire fault. In some valve models, we observe complex compound ruptures and swarm activity, which is linked to the ascent of a propagating fluid pressure pulse driven by a large increase in permeability during sliding. Both pump and valve mechanisms can produce anomalously weak faults, though they are each associated with distinctly different fluid pressure and strength evolution over the seismic cycle and during rupture. Our models highlight the complex way in which fluids may interact with earthquakes, especially if valve and pump models coexist.
Across Commas, Across Semicolons, Across Oceans: Presentation Style and Immigrant Dictionaries
Authors: Vrbinc Alenka , Farina Donna M T Cr , Vrbinc Marjeta
Published: May 2024

It is unfortunate that scholars have given scant attention to what can be called immigrant dictionaries. These books are significant to the history of (learner) lexicography; they meet pressing needs of immigrants and refugees. This article examines four immigrant dictionaries, Slovenian–English and English–Slovenian (Kubelka 1904, Kubelka 1912b, Košutnik 1912, and Kern 1919), published in the early twentieth century at a time when the Slovenian immigration to the United States was at its height. The presentation of information in these dictionaries is investigated with a focus on the treatment of homonymy, polysemy, conversion, and parenthetical information. Findings address the implications of a macrostructure-oriented versus a microstructure-oriented approach for immigrant user understanding. The paper recommends that learner lexicography should prioritize the design of the lexicographic presentation in the microstructure and prioritize the presentation of meaning over other possible elements covered traditionally in dictionaries.
Fall armyworm (Lepidoptera: Noctuidae): practical resistance of 2 Brazilian populations to Cry1A.105 + Cry2Ab and Cry1F Bt maize
Authors: Orozco-Restrepo Silvana M , Santos-Amaya Oscar F , Miranda Morgana de Souza , Tavares Clébson S , Pereira Eliseu José G
Published: May 2024

In the Americas, transgenic crops producing insecticidal proteins from Bacillus thuringiensis Berliner (Bt, Bacillales: Bacillaceae) have been used widely to manage fall armyworm (FAW, Spodoptera frugiperda [J.E. Smith]). As resistance to Cry1 single-gene Bt maize (Zea mays L.) rapidly evolved in some FAW populations, pyramided Bt maize hybrids producing Cry1, Cry2, or Vip3Aa proteins were introduced in the 2010s. We examined field-evolved resistance to single- and dual-protein Bt maize hybrids in 2 locations in southeastern Brazil, where plant damage by FAW larvae far exceeded the economic threshold in 2017. We collected late-instar larvae in Cry1A.105 + Cry2Ab and Cry1F maize fields and established 2 FAW populations in the laboratory. The F1 offspring reared on the foliage of Bt and non-Bt maize plants (Cry1A.105 + Cry2Ab and Cry1F) showed neonate-to-adult survival rates as high as 70% for both populations. There was no significant difference in the life-table parameters of armyworms reared on non-Bt and Bt maize foliage, indicating complete resistance to Cry1A.105 + Cry2Ab maize. Larval survival rates of reciprocal crosses of a susceptible laboratory strain and the field-collected populations indicated nonrecessive resistance to Cry1F and a recessive resistance to Cry1A.105 + Cry2Ab maize. When relaxing the selection pressure, the armyworm fitness varied on Cry1A.105 + Cry2Ab and non-Bt maize; the resistance was somewhat stable across 12 generations, without strong fitness costs, although one of the lines died confounded by a depleted-quality, artificial rearing diet. To our knowledge, this is the first report documenting the practical resistance of FAW to a pyramided Bt crop. We discuss the implications for resistance management.
Precision medicine for pancreatic cancer: characterizing the clinicogenomic landscape and outcomes of KRAS G12C-mutated disease
Authors: Keane Fergus , Chou Joanne F , Walch Henry , Schoenfeld Joshua , Singhal Anupriya , Cowzer Darren , Harrold Emily , O’Connor Catherine A , Park Wungki , Varghese Anna , El Dika Imane , Balogun Fiyinfolu , Yu Kenneth H , Capanu Marinela , Schultz Nikolaus , Yaeger Rona , O’Reilly Eileen M
Published: May 2024

Background

Mutated Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogene alteration in pancreatic ductal adenocarcinoma, and KRAS glycine to cystine substitution at codon 12 (G12C) mutations (KRAS G12Cmut) are observed in 1%-2%. Several inhibitors of KRAS G12C have recently demonstrated promise in solid tumors, including pancreatic cancer. Little is known regarding clinical, genomics, and outcome data of this population.

Methods

Patients with pancreatic cancer and KRAS G12Cmut were identified at Memorial Sloan Kettering Cancer Center and via the American Association of Cancer Research Project Genomics, Evidence, Neoplasia, Information, Exchange database. Clinical, treatment, genomic, and outcomes data were analyzed. A cohort of patients at Memorial Sloan Kettering Cancer Center with non-G12C KRAS pancreatic cancer was included for comparison.

Results

Among 3571 patients with pancreatic ductal adenocarcinoma, 39 (1.1%) with KRAS G12Cmut were identified. Median age was 67 years, and 56% were female. Median body mass index was 29.2 kg/m2, and 67% had a smoking history. Median overall survival was 13 months (95% CI: 9.4 months, not reached) for stage IV and 26 months (95% CI: 23 months, not reached) for stage I-III. Complete genomic data (via American Association of Cancer Research Project Genomics, Evidence, Neoplasia, Information, Exchange database) was available for 74 patients. Most common co-alterations included TP53 (73%), CDKN2A (33%), SMAD4 (28%), and ARID1A (21%). Compared with a large cohort (n = 2931) of non-G12C KRAS-mutated pancreatic ductal adenocarcinoma, ARID1A co-mutations were more frequent in KRAS G12Cmut (P < .05). Overall survival did not differ between KRAS G12Cmut and non-G12C KRAS pancreatic ductal adenocarcinoma. Germline pathogenic variants were identified in 17% of patients; 2 patients received KRAS G12C-directed therapy.

Conclusion

Pancreatic cancer and KRAS G12Cmut may be associated with a distinct clinical phenotype. Genomic features are similar to non-G12C KRAS-mutated pancreatic cancer, although enrichment of ARID1A co-mutations was observed. Targeting of KRAS G12C in pancreatic cancer provides a precedent for broader KRAS targeting in pancreatic cancer.
Identification of TP53 germline variants in pediatric patients undergoing tumor testing: strategy and prevalence
Authors: Luo Minjie , Wong Derek , Zelley Kristin , Wu Jinhua , Schubert Jeffery , Denenberg Elizabeth H , Fanning Elizabeth A , Chen Jiani , Gallo Daniel , Golenberg Netta , Patel Maha , Conlin Laura K , Maxwell Kara N , Wertheim Gerald B , Surrey Lea F , Zhong Yiming , Brodeur Garrett M , MacFarland Suzanne P , Li Marilyn M
Published: May 2024

Background

TP53 alterations are common in certain pediatric cancers, making identification of putative germline variants through tumor genomic profiling crucial for disease management.

Methods

We analyzed TP53 alterations in 3123 tumors from 2788 pediatric patients sequenced using tumor-only or tumor-normal paired panels. Germline confirmatory testing was performed when indicated. Somatic and germline variants were classified based on published guidelines.

Results

In 248 tumors from 222 patients, 284 tier 1/2 TP53 sequence and small copy number variants were detected. Following germline classification, 86.6% of 142 unique variants were pathogenic or likely pathogenic. Confirmatory testing on 118 patients revealed germline TP53 variants in 28 of them (23 pathogenic or likely pathogenic and 5 of uncertain significance), suggesting a minimum Li-Fraumeni syndrome incidence of 0.8% (23/2788) in this cohort, 10.4% (23/222) in patients with TP53 variant–carrying tumors, and 19.5% (23/118) with available normal samples. About 25% (7/28) of patients with germline TP53 variants did not meet Li-Fraumeni syndrome diagnostic or testing criteria, while 20.9% (28/134) with confirmed or inferred somatic origins did. TP53 biallelic inactivation occurred in 75% of germline carrier tumors and was also prevalent in other groups, causing an elevated tumor-observed variant allelic fraction. Somatic evidence, however, including low variant allele fraction correctly identified only 27.8% (25/90) of patients with confirmed somatic TP53 variants.

Conclusion

The high incidence and variable phenotype of Li-Fraumeni syndrome in this cohort highlights the importance of assessing germline status of TP53 variants identified in all pediatric tumors. Without clear somatic evidence, distinguishing somatic from germline origins is challenging. Classifying germline and somatic variants should follow appropriate guidelines.
Removal of a large symptomatic retrocardiac mediastinal lipoma
Authors: Wollheim Martina , Willatt Lily F S , Ehrsam Jonas P , Cerncic Priska , Lachat Mario L , Schöb Othmar , Inci Ilhan
Published: May 2024

Large mediastinal lipomas are rare. Complete surgical resection can be difficult due to the intricate anatomy in the mediastinum. We report the case of a 75-year-old man with worsened retrosternal pressure, decline in performance and syncope episodes. Computed tomography revealed a large retrocardiac low-attenuated mediastinal lesion measuring 10 × 8 cm, compressing the left atrium and pulmonary veins bilaterally. Surgical exploration was achieved through a right anterolateral thoracotomy with a successful en bloc resection without any intraoperative complications. The total operation time was 185 min with a total blood loss of <250 ml. Stand-by extracorporeal life support was present throughout the procedure, but its use was not required. The postoperative course was uneventful. The pathological examination revealed a mature mediastinal lipoma without any evidence of malignancy. In the 12-month control the patient was completely free of symptoms and in a good general condition.
Gastrointestinal basidiobolomycosis: a rare manifestation of Basidiobolus ranarum in a non-endemic region
Authors: Fathaddin Amany , Alobaid Sarah , Alhumoudi Duaa , Almarshoud Ghaida , Alsubaie Abdulaziz , Alotaibi Naif H
Published: May 2024

Gastrointestinal basidiobolomycosis (GIB) is a rare fungal infection caused by the Basidiobolus ranarum, and it possesses a significant challenge to diagnose it as it presents with non-specific symptoms that often mimic cancer. Herein, we report a case of GIB in a 51-year-old male from the central region of Saudi Arabia, a non-endemic region of GIB, which was initially misdiagnosed as colon cancer. A 51-year-old man presented with abdominal pain for two-months, non-bloody diarrhea, loss of appetite, and weight loss. Abdominal examination revealed a large mass measuring ~10x15cm. Radiological findings prompted the diagnosis of a colon mass, and the patient was surgically treated under that impression. Hemicolectomy and end colostomy with mucous fistula from distal sigmoid stump were done. Histopathology was consistent with GIB. The diagnosis of GIB presents a serious challenge and requires a high index of clinical suspicion.
An unusual presentation of penile fracture with complete transection of urethra: a case report
Authors: Dunna Vasanth , Giduturi Srinivasa Rao , Chary K S N , Kutikuppala L V Simhachalam , Jose Anna Mary , Golla Varshitha
Published: May 2024

Penile fracture is one such urologic emergency that occurs when the penis is struck bluntly during sexual activity, and in less than 5–10% of cases, the concurrent urethral damage is evident, but complete transection is very rare. A 37-year-old male presented with a history of ‘snap’ sound and immediate detumescence of penis during intercourse, when he fell and hit the pubic bone of his partner. There was acute retention of urine, an attempt to pass a catheter failed and the patient underwent supra-pubic catheterization. On examination, there was classical ‘eggplant deformity’ of the penis with blood at the tip of the meatus. MRI showed a tunical tear on both sides at the penoscrotal junction with indistinct urethra and extensive hematoma in the proximal penile shaft. Surgical management was successfully done by anastomotic urethroplasty and cavernosal repair.
Theoretical investigation of energy levels and transitions for Ce iii with applications to kilonova spectra
Authors: Gaigalas G , Rynkun P , Domoto N , Tanaka M , Kato D , Kitovienė L
Published: May 2024

Doubly ionized cerium (Ce2+) is one of the most important ions to understand the kilonova spectra. In particular, near-infrared (NIR) transitions of Ce iii between the ground (5p6 4f2) and first excited (5p6 4f 5d) configurations are responsible for the absorption features around 14 500 Å. However, there is no dedicated theoretical studies to provide accurate transition probabilities for these transitions. We present energy levels of the ground and first excited configurations and transition data between them for Ce iii. Calculations are performed using the grasp2018 package, which is based on the multiconfiguration Dirac–Hartree–Fock and relativistic configuration interaction methods. Compared with the energy levels in the NIST data base (Kramida et al. 2024), our calculations reach the accuracy with the root-mean-square (rms) of 2732 or 1404 cm−1 (excluding one highest level) for ground configuration, and rms of 618 cm−1 for the first excited configuration. We extensively study the line strengths and find that the Babushkin gauge provides the more accurate values. By using the calculated gf values, we show that the NIR spectral features of kilonova can be explained by the Ce iii lines.
Unveiling the X-ray polarimetric properties of LMC X−3 with IXPE, NICER, and Swift/XRT
Authors: Garg Akash , Rawat Divya , Méndez Mariano
Published: May 2024

The incoming Imaging X-ray Polarimetry Explorer (IXPE) observations of X-ray binaries provide a new tool to investigate the underlying accretion geometry. Here, we report the first measurements of X-ray polarization of the extragalactic black-hole X-ray binary LMC X−3. We find a polarization fraction of $\sim 3~{{\ \rm per\ cent}}$ at a polarization angle of ∼135° in the 2–8 keV energy band with statistical significance at the 7σ level. This polarization measurement significantly exceeds the minimum detectable polarization threshold of 1.2 per cent for the source, ascertained at a 99 per cent confidence level within the 2–8 keV energy band. The simultaneous spectro-polarimetric fitting of Neutron Star Interior Composition Explorer, Swift/X-Ray Telescope (XRT), and IXPE revealed the presence of a disc with a temperature of ∼1 keV and a Comptonized component with a power-law index of ∼2.4, confirming the soft nature of the source. The polarization degree increases with energy from ∼3 per cent in the 2–5.7 keV band to ∼9 per cent in the 5.7–8 keV band, while the polarization angle is energy independent. The observed energy dependence and the sudden jump of polarization fraction above 5 keV supports the idea of a static slab coronal geometry for the Comptonizing medium of LMC X−3.
Second Time's the Charm? Assessing the Sensitivity and Yield of Inpatient Diagnostic Algorithms for Pulmonary Tuberculosis in a Low-Prevalence Setting
Authors: Dugdale Caitlin M , Zachary Kimon C , McEvoy Dustin S , Branda John A , Courtney Amy , Craig Rebecca , Doms Alexandra , Germaine Lindsay , Green Chloe V , Gulbas Eren , Hooper David C , Hurtado Rocio M , Hyle Emily P , Jerry Michelle S , Lazarus Jacob E , Paras Molly , Turbett Sarah E , Shenoy Erica S
Published: May 2024

Background

For persons with suspected pulmonary tuberculosis, the guidelines of the Centers for Disease Control and Prevention recommend collecting 3 respiratory specimens 8 to 24 hours apart for acid-fast bacilli (AFB) smear and culture, in addition to 1 nucleic acid amplification test (NAAT). However, data supporting this approach are limited. Our objective was to estimate the performance of 1, 2, or 3 AFB smears with or without NAATs to detect pulmonary tuberculosis in a low-prevalence setting.

Methods

We conducted a retrospective study of hospitalized persons at 8 Massachusetts acute care facilities who underwent mycobacterial culture on 1 or more respiratory specimens between July 2016 and December 2022. We evaluated percentage positivity and yield on serial AFB smears and NAATs among people with growth of Mycobacterium tuberculosis on mycobacterial cultures.

Results

Among 104 participants with culture-confirmed pulmonary tuberculosis, the first AFB smear was positive in 41 cases (39%). A second AFB smear was positive in 11 (22%) of the 49 cases in which it was performed. No third AFB smears were positive following 2 initial negative smears. Of 52 smear-negative cases, 36 had a NAAT performed, leading to 23 additional diagnoses. Overall sensitivity to detect tuberculosis prior to culture positivity was higher in any strategy involving 1 or 2 NAATs (74%–79%), even without AFB smears, as compared with 3 smears alone (60%).

Conclusions

Tuberculosis diagnostic testing with 2 AFB smears offered the same yield as 3 AFB smears while potentially reducing laboratory burden and duration of airborne infection isolation. Use of 1 or 2 NAATs increased sensitivity to detect culture-positive pulmonary tuberculosis when added to AFB smear–based diagnostic testing alone.
Under ice plankton and lipid dynamics in a subarctic lake
Authors: Kers Erwin , Leu Eva , Amundsen Per-Arne , Primicerio Raul , Kainz Martin , Poste Amanda E
Published: May 2024

Climate warming causes shorter winters and changes in ice and snow cover in subarctic lakes, highlighting the need to better understand under-ice ecosystem functioning. The plankton community in a subarctic, oligotrophic lake was studied throughout the ice-covered season, focusing on lipid dynamics and life history traits in two actively overwintering copepods, Cyclops scutifer and Eudiaptomus graciloides. Whereas C. scutifer was overwintering in C-IV to C-V stage, E. graciloides reproduced under ice cover. Both species had accumulated lipids prior to ice-on and showed a substantial decrease in total lipid content throughout the ice-covered period: E. graciloides (60%–38% dw) and C. scutifer (73%–33% dw). Polyunsaturated fatty acids of algal origin were highest in E. graciloides and declined strongly in both species. Stearidonic acid (18:4n-3) content in E. graciloides was particularly high and decreased rapidly during the study period by 50%, probably due to reproduction. The copepods differed in feeding behavior, with the omnivore C. scutifer continuing to accumulate lipids until January, whereas the herbivorous E. graciloides accumulated lipids from under-ice primary production during the last months of ice-cover. Our findings emphasize the importance of lipid accumulation and utilization for actively overwintering copepods irrespective of the timing of their reproduction.
Asiatic acid alleviates vascular remodeling inBAPN‐induced aortic dissection through inhibitingNF‐κBp65/CX3CL1signaling
Authors: Zhang Heng , Li Yubin , Liu Mingyuan , Guo Mingjin , Zhang Ruipeng , Zhao Kaiwen , Wu Jianlie , Zhao Zhenyuan , Zhu Hongqiao , Liu Junjun
Published: May 2024

Inflammation assumes a pivotal role in the aortic remodeling of aortic dissection (AD). Asiatic acid (AA), a triterpene compound, is recognized for its strong anti‐inflammatory properties. Yet, its effects on β‐aminopropionitrile (BAPN)‐triggered AD have not been clearly established. The objective is to determine whether AA attenuates adverse aortic remodeling in BAPN‐induced AD and clarify potential molecular mechanisms. In vitro studies, RAW264.7 cells pretreated with AA were challenged with lipopolysaccharide (LPS), and then the vascular smooth muscle cells (VSMCs)‐macrophage coculture system was established to explore intercellular interactions. To induce AD, male C57BL/6J mice at three weeks of age were administered BAPN at a dosage of 1 g/kg/d for four weeks. To decipher the mechanism underlying the effects of AA, RNA sequencing analysis was conducted, with subsequent validation of these pathways through cellular experiments. AA exhibited significant suppression of M1 macrophage polarization. In the cell coculture system, AA facilitated the transformation of VSMCs into a contractile phenotype. In the mouse model of AD, AA strikingly prevented the BAPN‐induced increases in inflammation cell infiltration and extracellular matrix degradation. Mechanistically, RNA sequencing analysis revealed a substantial upregulation of CX3CL1 expression in BAPN group but downregulation in AA‐treated group. Additionally, it was observed that the upregulation of CX3CL1 negated the beneficial impact of AA on the polarization of macrophages and the phenotypic transformation of VSMCs. Crucially, our findings revealed that AA is capable of downregulating CX3CL1 expression, accomplishing this by obstructing the nuclear translocation of NF‐κB p65. The findings indicate that AA holds promise as a prospective treatment for adverse aortic remodeling by suppressing the activity of NF‐κB p65/CX3CL1 signaling pathway.
Self-rated health and risk of incident cardiovascular events among individuals with hypertension
Authors: Kazibwe Richard , Muhammad Ahmad Imtiaz , Singleton Matthew J. , Evans Joni K. , Chevli Parag A. , Namutebi Juliana H. , Kazibwe Joseph , Epiu Isabella , German Charles , Soliman Elsayed Z. , Shapiro Michael D. , Yeboah Joseph
Published: May 2024

Background:

The relationship between self-rated health (SRH) and cardiovascular events in individuals with hypertension, but without diabetes mellitus, is understudied.

Methods:

We performed a post hoc analysis of data from SPRINT (Systolic Blood Pressure Intervention Trial). SRH was categorized into excellent, very good, good and fair/poor. Using multivariable Cox regression, we estimated hazard ratios and 95% confidence intervals (CIs) for the association of SRH with both all-cause mortality and a composite of cardiovascular events (the primary outcome), which was defined to include myocardial infarction (MI), other acute coronary syndromes, stroke, acute decompensated heart failure, and cardiovascular death.

Results:

We included 9319 SPRINT participants (aged 67.9 ± 9 years, 35.6% women) with a median follow-up of 3.8 years. Compared with SRH of excellent, the risk [hazard ratio (95% CI)] of the primary outcome associated with very good, good, and fair/poor SRH was 1.11(0.78–1.56), 1.45 (1.03–2.05), and 1.87(1.28–2.75), respectively. Similarly, compared with SRH of excellent, the risk of all-cause mortality [hazard ratio (95% CI)] associated with very good, good, and fair/poor SRH was 1.13 (0.73–1.76), 1.72 (1.12–2.64), and 2.11 (1.32–3.38), respectively. Less favorable SRH (LF-SRH) was also associated with a higher risk of each component of the primary outcome and serious adverse events (SAE).

Conclusion:

Among individuals with hypertension, SRH is independently associated with the risk of incident cardiovascular events, all-cause mortality, and SAE. Our study suggest that guidelines should consider the potential significance of including SRH in the clinical history of patients with hypertension.
A comparative radiographic study of bone density changes around titanium implants in the posterior mandible, preoperative, and postoperative
Authors: Issa Nazih S.H. , Othman Tarafa A. , Sleman Batoul M.
Published: May 2024

Background:

Implant success and the state of the surrounding bone require multiple measures, especially in humans, and this study aimed to identify the development of the state of the latter by means of radiographic examination performed during the period of osseointegration as well as investigate the changes in bone density that occur after implant installation and 2 months after functional loading. Implant success rates are affected by bone density at the implant site. Therefore, understanding changes in bone density after dental implant placement is essential, as it correlates with subsequent implant success.

Materials and methods:

Digital radiographs of 28 implants were taken and evaluated at four intervals: preoperatively, 1 and 3 months postoperatively, and 2 months following placement of the permanent prosthesis. Gray values were measured in different areas around the implants through analyzing X-ray images and measuring bone density around the implants using EzDent – 2D software. The aim of this study was to investigate changes in bone density around implants in three regions: apex, neck, and body, as well as to record average density values during the observation period by measuring digital image gray levels (the gray values of the digital radiographs). This was conducted to determine local bone densities in dental implant recipient sites and to study changes in local bone densities at different intervals, preoperatively and postoperatively and after placement of the prosthesis.

Results:

A decrease was observed in gray values proportional to reference values 1-month after implant insertion, but these increased at 3 months after insertion and continued to rise 2 months after placement of the prosthesis in the apical, body, and neck regions of the implant.

Conclusion:

Sensor-tuned radiography can be used as an effective method to support clinical follow-ups as well as measure changes in bone densities around implants in critical cases.
Differential expression of plasma proteins in pregnant women exposed toPlasmodium falciparummalaria
Authors: Kanoi Bernard N. , Waweru Harrison , Kobia Francis M. , Mukala Joseph , Kirira Peter , Mogere Dominic , Gallini Radiosa , Åberg Mikael , Vatish Manu , Gitaka Jesse , Kamali-Moghaddam Masood
Published: May 2024

In sub-Saharan Africa, pregnant women are at greater risk of malaria infection than non-pregnant adult women. The infection may lead to pregnancy-associated malaria (PAM) because of the sequestration ofPlasmodium falciparum-infected erythrocytes in the placental intervillous space. Although there are several tools for diagnosing malaria infection during pregnancy, including blood smear microscopic examination, rapid diagnostic tests, and PCR, there are no tools for detecting placental infection and, by extension, any dysfunction associated with PAM. Thus, PAM, specifically placental infection, can only be confirmed via postnatal placental histopathology. Therefore, there is an urgent need for specific serum biomarkers of PAM. Here, we used the high throughput proximity extension assay to screen plasma from malaria-exposed pregnant women for differentially expressed proteins that can predict PAM or adverse malaria outcomes. Such biomarkers may also elucidate the pathophysiology of PAM. We observed that the IgG Fc receptor IIb (Uniprot ID P31994) and HO-1 (P09601) are consistently highly expressed in malaria-positive samples compared to samples from malaria-negative pregnant women. On the contrary, NRTN (Q99748) and IL-20 (Q9NYY1) were differentially expressed in the malaria-negative women. IL-20 exhibited the highest discriminatory power (AUC = 0.815), indicating a strong association with malaria status. These proteins should be considered for further evaluation as biomarkers of malaria-induced placental dysfunction in pregnant women.
Genome-wide Mendelian Randomization Identifies Potential Drug Targets for Dorsopathies
Authors: Cui Yu , Guo Jiarui , Lu Yuanxi , Hu Mengting , Zhou He , Zhang Wancong , Tang Shijie
Published: May 2024

Background

Dorsopathies are a group of musculoskeletal disorders affecting the spinal column and related structures, contributing significantly to global disability rates and healthcare costs. Despite their prevalence, the genetic and biological mechanisms underlying dorsopathies are not fully understood.

Method

Summary-data-based Mendelian Randomization (SMR) and colocalization analysis were employed, using data from genome-wide association studies (GWAS) and cis-expression quantitative trait loci (cis-eQTLs) databases. Genes with a colocalization posterior probability (PP.H4) above 0.7 in SMR results were selected for additional analysis. These selected genes underwent MR analysis to examine possible causal connections with dorsopathies, and sensitivity analyses were carried out to ensure robustness. Additionally, two transcriptome-wide association studies (TWAS) were utilized to confirm and screen for potential drug targets.

Result

We identified four essential genes linked to dorsopathies:NLRC4,CGREF1,KHK, andRNF212. Mendelian randomization (MR) analysis revealed a potential causal link between these genes and dorsopathies. Elevated transcription levels ofNLRC4,CGREF1, andKHKcorrelated with reduced dorsopathies risk, while increased levels ofRNF212were associated with heightened risk of dorsopathies. Regarding methylation sites, an increase incg04686953fully mediated the decreased risk of dorsopathies byRNF212. Similarly, the risk effect ofcg26638505andcg18948125was entirely mediated byNLRC4, whileCGREF1predominantly mediated the risk-increasing effect ofcg06112415and the decrease effect ofcg22740783.

Conclusion

Dorsopathies were associated with four pivotal genes:NLRC4,CGREF1,KHK, andRNF212. Methylation analysis identified cg04686953 andcg22740783as protective against dorsopathies risk, whilecg26638505,cg18948125, andcg06112415exhibited a risk-increasing impact.
Enhanced Detection and Genotyping of Disease-Associated Tandem Repeats Using HMMSTR and Targeted Long-Read Sequencing
Authors: Van Deynze Kinsey , Mumm Camille , Maltby Connor J. , Switzenberg Jessica A. , Todd Peter K. , Boyle Alan P.
Published: May 2024

Tandem repeat sequences comprise approximately 8% of the human genome and are linked to more than 50 neurodegenerative disorders. Accurate characterization of disease-associated repeat loci remains resource intensive and often lacks high resolution genotype calls. We introduce a multiplexed, targeted nanopore sequencing panel and HMMSTR, a sequence-based tandem repeat copy number caller. HMMSTR outperforms current signal- and sequence-based callers relative to two assemblies and we show it performs with high accuracy in heterozygous regions and at low read coverage. The flexible panel allows us to capture disease associated regions at an average coverage of >150x. Using these tools, we successfully characterize known or suspected repeat expansions in patient derived samples. In these samples we also identify unexpected expanded alleles at tandem repeat loci not previously associated with the underlying diagnosis. This genotyping approach for tandem repeat expansions is scalable, simple, flexible, and accurate, offering significant potential for diagnostic applications and investigation of expansion co-occurrence in neurodegenerative disorders.

Abstract Figure
Investigating the Impact of Segregation and Integration on Infection Dynamics: Analysis of a Cholera Model in a Two-Population System
Authors: El Deeb Omar , Matar Antoine
Published: May 2024

We present a novel dynamic model designed to depict Cholera outbreaks within a two-population framework featuring two environmental reservoirs. The model is designed to emulate the impact of segregation or integration between two populations on the transmission of the disease and infections throughout the entire community, both with and without non-medicinal interventions. This is achieved by allowing infectious individuals to interact with the reservoir of the alternate population at different levels of suppression, in addition to their regular interaction with their own reservoir.

We find out that increased suppression of cross community interaction reduces the number of infections in the overall population as well as in the population with less contamination and contact. Additionally, we predict significant delays in the occurrence of peak infections, affording public health authorities crucial time for intervention. Lowering cross-immunity interactions also leads to a decrease in bacterial concentrations in environmental reservoirs. Finally, we demonstrate that non-medicinal interventions, including sanitation and water purification, would significantly reduce and delay infections, providing a valuable time frame for implementing additional medicinal measures.
Genome-wide study of gene-by-sex interactions identifies risks for cleft palate
Authors: Robinson Kelsey , Parrish Randy , Adeyemo Wasiu Lanre , Beaty Terri H. , Butali Azeez , Buxó Carmen J. , Gowans Lord JJ , Hecht Jacqueline T. , Moreno Lina , Murray Jeffrey C. , Shaw Gary M. , Weinberg Seth M. , Brand Harrison , Marazita Mary L. , Cutler David J. , Epstein Michael P. , Yang Jingjing , Leslie Elizabeth J.
Published: May 2024

Structural birth defects affect 3-4% of all live births and, depending on the type, tend to manifest in a sex-biased manner. Orofacial clefts (OFCs) are the most common craniofacial structural birth defects and are often divided into cleft lip with or without cleft palate (CL/P) and cleft palate only (CP). Previous studies have found sex-specific risks for CL/P, but these risks have yet to be evaluated in CP. CL/P is more common in males and CP is more frequently observed in females, so we hypothesized there would also be sex-specific differences for CP. Using a trio-based cohort, we performed sex-stratified genome-wide association studies (GWAS) based on proband sex followed by a genome-wide gene-by-sex (GxS) interaction testing. There were 13 loci significant for GxS interactions, with the top finding inLTBP1(RR=3.37 [2.04 - 5.56], p=1.93x10-6). LTBP1 plays a role in regulating TGF-B bioavailability, and knockdown in both mice and zebrafish lead to craniofacial anomalies. Further, there is evidence for differential expression ofLTBP1between males and females in both mice and humans. Therefore, we tested the association between the imputed genetically regulated gene expression of genes with significant GxS interactions and the CP phenotype. We found significant association forLTBP1in cell cultured fibroblasts in female probands (p=0.0013) but not in males. Taken altogether, we show there are sex-specific risks for CP that are otherwise undetectable in a combined sex cohort, andLTBP1is a candidate risk gene, particularly in females.
Treatment of Spontaneous Subarachnoid Hemorrhage: A 20-year National Inpatient Sample Review
Authors: Feler Joshua , Wolman Dylan , Torabi Radmehr , Chen Jia-Shu , Teshome Abigail , Sastry Rahul , Doberstein Curtis , Jayaraman Mahesh , Moldovan Krisztina , Mahta Ali
Published: May 2024

Background

Aneurysmal subarachnoid hemorrhage is a major source of morbidity and mortality, and its management has undergone foundational changes over the last 2 decades. We reviewed the National Inpatient Sample (NIS) to outline the changes in severity of illness, surgical management, and patient outcomes over time.

Methods

A retrospective cohort of admissions for spontaneous subarachnoid hemorrhage (SAH) in the NIS from 2001-2020 was reviewed, including those that underwent microsurgical or endovascular surgery to secure a ruptured aneurysm. National incidence was calculated, and multivariable regression was used to identify changes in incidence and outcome through time, segmented by epoch.

Results

Review of the NIS identified 450,723 SAH patients, of which 182,151 underwent surgical aneurysm treatment. The incidence of spontaneous SAH fell −0.127 per 100,000 person-years each year [95%CI: −0.164, −0.0887]). Among patients surgically treated for aneurysmal SAH, the proportion of patients <50 years old fell from 40% to 30% between first and final epochs, and the proportion of those in the lowest stroke scale category, roughly equivalent to Hunt & Hess grade 1 or 2, fell from 68% to 49%. The proportion treated by microsurgery fell from 70% to 23% in favor of endovascular surgery. Hospital mortality among these treated cases was stable at 13% throughout the study period despite increasing illness severity indices. After adjustment, there was a 41% reduction of odds of hospital mortality in the final epoch compared with the first.

Conclusions

The incidence of hospitalization for spontaneous SAH fell between 2001 and 2020. Patients undergoing surgery to secure an aneurysm were more severely ill through time yet experienced a stable hospital mortality rate.
Velociraptor: Cross-Platform Quantitative Search Using Hallmark Cell Features
Authors: Cross Claire E , Mayeda Cass , Medina Stephanie , Hayes Madeline J , Kaviany Saara , Connelly James A , Rathmell Jeffrey C , Weaver Kyle D , Thompson Reid C , Chambless Lola B , Ihrie Rebecca A , Irish Jonathan M
Published: May 2024

A key challenge for single cell discovery analysis is to identify new cell types, describe them quantitatively, and seek these novel cells in new studies often using a different platform. Over the last decade, tools were developed to address identification and quantitative description of cells in human tissues and tumors. However, automated validation of populations at the single cell level has struggled due to the cytometry field's reliance on hierarchical, ordered use of features and on platform-specific rules for data processing and analysis. Here we present Velociraptor, a workflow that implements Marker Enrichment Modeling in three cross-platform modules: 1) identification of cells specific to disease states, 2) description of hallmark features for each cell and population, and 3) searching for cells matching one or more hallmark feature sets in a new dataset. A key advance is that Velociraptor registers cells between datasets, including between flow cytometry and quantitative imaging using different, overlapping feature sets. Four datasets were used to challenge Velociraptor and reveal new biological insights. Working at the individual sample level, Velociraptor tracked the abundance of clinically significant glioblastoma brain tumor cell subsets and characterized the cells that predominate in recurrent tumors as a close match for rare, negative prognostic cells originally observed in matched pre-treatment tumors. In patients with inborn errors of immunity, Velociraptor identified genotype-specific cells associated withGATA2haploinsufficiency. Finally, in cross-platform analysis of immune cells in multiplex imaging of breast cancer, Velociraptor sought and correctly identified memory T cell subsets in tumors. Different phenotypic descriptions generated by algorithms or humans were shown to be effective as search inputs, indicating that cell identity need not be described in terms of per-feature cutoffs or strict hierarchical analyses. Velociraptor thus identifies cells based on hallmark feature sets, such as protein expression signatures, and works effectively with data from multiple sources, including suspension flow cytometry, imaging, and search text based on known or theoretical cell features.
Evidence that the SARS-CoV-2 S protein undergoes a conformational change at the Golgi Complex that leads to the formation of virus neutralising antibody binding epitopes in the S1 protein subunit.
Authors: Sugrue Richard J , Tan Boon Huan , Lai Soak Kuan , Chan Conrad En-Zuo , Wu Yanjun
Published: May 2024

Recombinant SARS-CoV-2 S protein expression was examined in Vero cells by imaging using the human monoclonal antibody panel (PD4, PD5, sc23, and sc29). The PD4 and sc29 antibodies recognised conformational specific epitopes in the S2 protein subunit at the Endoplasmic reticulum and Golgi complex. While PD5 and sc23 detected conformationally specific epitopes in the S1 protein subunit at the Golgi complex, only PD5 recognised the receptor binding domain (RBD). A comparison of the staining patterns of PD5 with non-conformationally specific antibodies that recognises the S1 subunit and RBD suggested the PD5 recognised a conformational structure within the S1 protein subunit. Our data suggests the antibody binding epitopes recognised by the human monoclonal antibodies formed at different locations in the secretory pathway during S protein transport, but a conformational change in the S1 protein subunit at the Golgi complex formed antibody binding epitopes that are recognised by virus neutralizing antibodies