bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of nomogram model for the prediction of esophageal variceal hemorrhage in hepatitis B-induced hepatic cirrhosis
Authors: Xu Jing , Tan Lin , Jiang Ning , Li Fengcheng , Wang Jinling , Wang Beibei , Li Shasha
Published: April 2024

Background

Esophageal variceal (EV) hemorrhage is a life-threatening consequence of portal hypertension in hepatitis B virus (HBV) -induced cirrhotic patients. Screening upper endoscopy and endoscopic variceal ligation to find EVs for treatment have complications, contraindications, and high costs. We sought to identify the nomogram models (NMs) as alternative predictions for the risk of EV hemorrhage.

Methods

In this case-control study, we retrospectively analyzed 241 HBV-induced liver cirrhotic patients treated for EVs at the Second People’s Hospital of Fuyang City, China from January 2021 to April 2023. We applied univariate analysis and multivariate logistic regression to assess the accuracy of various NMs in EV hemorrhage. The area under the curve (AUC) and calibration curves of the receiver’s operating characteristics were used to evaluate the predictive accuracy of the nomogram. Decision curve analysis (DCA) was used to determine the clinically relevant of nomograms.

Results

In the prediction group, multivariate logistic regression analysis identified platelet distribution and spleen length as independent risk factors for EVs. We applied NMs as the independent risk factors to predict EVs risk. The NMs fit well with the calibration curve and have good discrimination ability. The AUC and DCA demonstrated that NMs with a good net benefit. The above results were validated in the validation cohort.

Conclusion

Our non-invasive NMs based on the platelet distribution width and spleen length may be used to predict EV hemorrhage in HBV-induced cirrhotic patients. NMs can help clinicians to increase diagnostic performance leading to improved treatment measures.
An assessment of risk factors for recurrence and survival for patients undergoing liver resection for intrahepatic cholangiocarcinoma
Authors: Öztürk Nazli Begüm , Jamil Laith H.
Published: April 2024

Background and aims

Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver malignancy with increasing rates of incidence and mortality. Surgical resection is curative for patients who are diagnosed at early stages of iCCA. Limited data exist regarding risk factors for postresection recurrence and overall survival as iCCA is rare, and majority of patients are diagnosed at an advanced stage and thus not candidates for resection. We aimed to analyze clinical and laboratory characteristics, tumor histology, locoregional invasion, recurrence and survival in patients undergoing curative resection for iCCA.

Methods

All patients who underwent curative resection for iCCA between 2006 and 2023 at our institution were included in the study. Clinical characteristics, laboratory, histological and follow-up data were collected.

Results

The 1-, 3-, and, 5-year survival rates were 90.9%, 65.9% and 44.2%, respectively. About 65.6% of patients had recurrence in a median of 1.2 years after liver resection. Positive surgical margins were present in 20.73% of patients. Notably, 80.51% had solitary tumor and the remaining 19.48% had multifocal tumor. A total of 64.51% of patients received adjuvant chemotherapy after resection. A total of 26 (31.3%) patients had died during the follow-up period. Duration from liver resection to last follow-up or death was 1.6 years (0.8–3.2). Overall median survival was 4.6 years. The presence of lymph node metastases, vascular invasion, positive surgical margin and advanced tumor stage at diagnosis were associated with significantly worse overall survival, which remained significant in multivariable model for advanced tumor stage and positive surgical margin.

Conclusion

Despite curative resection, recurrence rate is high and overall survival is poor in patients with iCCA. Real-world data regarding patient characteristics and longitudinal follow-up remain important as iCCA is a rare malignancy.
Time Course of Mechanical Ventilation Driving Pressure Levels in Pediatric Acute Respiratory Distress Syndrome: Outcomes in a Prospective, Multicenter Cohort Study From Colombia, 2018–2022
Authors: Fernández-Sarmiento Jaime , Bejarano-Quintero Ana María , Tibaduiza Jose Daniel , Moreno-Medina Karen , Pardo Rosalba , Mejía Luz Marina , Junco Jose Luis , Rojas Jorge , Peña Oscar , Martínez Yomara , Izquierdo Ledys , Guzmán Maria Claudia , Vásquez-Hoyos Pablo , Molano Milton , Gallon Carlos , Bonilla Carolina , Fernández-Palacio Maria Carolina , Merino Valentina , Bernal Christian , Fernández-Sarta Juan Pablo , Hernandez Estefanía , Alvarez Isabela , Tobo Juan Camilo , Beltrán Maria Camila , Ortiz Juanita , Botia Laura , Fernández-Rengifo Jose Manuel , del Pilar Pereira-Ospina Rocio , Blundell Alexandra , Nieto Andres , Duque-Arango Catalina
Published: April 2024

OBJECTIVES:

High driving pressure (DP, ratio of tidal volume (Vt) over respiratory system compliance) is a risk for poor outcomes in patients with pediatric acute respiratory distress syndrome (PARDS). We therefore assessed the time course in level of DP (i.e., 24, 48, and 72 hr) after starting mechanical ventilation (MV), and its association with 28-day mortality.

DESIGN:

Multicenter, prospective study conducted between February 2018 and December 2022.

SETTING:

Twelve tertiary care PICUs in Colombia.

PATIENTS:

One hundred eighty-four intubated children with moderate to severe PARDS.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

The median (interquartile range [IQR]) age of the PARDS cohort was 11 (IQR 3–24) months. A total of 129 of 184 patients (70.2%) had a pulmonary etiology leading to PARDS, and 31 of 184 patients (16.8%) died. In the first 24 hours after admission, the plateau pressure in the nonsurvivor group, compared with the survivor group, differed (28.24 [IQR 24.14–32.11] vs. 23.18 [IQR 20.72–27.13] cm H2O,p< 0.01). Of note, children with a Vtless than 8 mL/kg of ideal body weight had lower adjusted odds ratio (aOR [95% CI]) of 28-day mortality (aOR 0.69, [95% CI, 0.55–0.87];p= 0.02). However, we failed to identify an association between DP level and the oxygenation index (aOR 0.58; 95% CI, 0.21–1.58) at each of time point. In a diagnostic exploratory analysis, we found that DP greater than 15 cm H2O at 72 hours was an explanatory variable for mortality, with area under the receiver operating characteristic curve of 0.83 (95% CI, 0.74–0.89); there was also increased hazard for death with hazard ratio 2.5 (95% CI, 1.07–5.92). DP greater than 15 cm H2O at 72 hours was also associated with longer duration of MV (10 [IQR 7–14] vs. 7 [IQR 5–10] d;p= 0.02).

CONCLUSIONS:

In children with moderate to severe PARDS, a DP greater than 15 cm H2O at 72 hours after the initiation of MV is associated with greater odds of 28-day mortality and a longer duration of MV. DP should be considered a variable worth monitoring during protective ventilation for PARDS.
Putting the Vicious Cycle to the Test: Evidence for the Cognitive Behavioral Model of Persistent Somatic Symptoms From an Online Study
Authors: Sahm Alexander H. J. , Witthöft Michael , Bailer Josef , Mier Daniela
Published: April 2024

Objective

In clinical practice, persistent somatic symptoms are regularly explained using a cognitive-behavioral model (CBM). In the CBM, predisposing, perpetuating, and precipitating factors are assumed to interact and to cause the onset and endurance of somatic symptoms. However, these models are rarely investigated in their entirety.

Methods

We conducted an online survey during the COVID-19 pandemic. A total of 2114 participants from the general German population completed questionnaires that measured different factors of the CBM. We used state negative affectivity and neuroticism as predisposing factors, fear of a COVID-19 infection as the precipitating factor, and somatic symptoms, misinterpretation of bodily symptoms, attention allocation to bodily symptoms, and health anxiety as perpetuating factors. Moreover, we added safety and avoidance behavior as end points to the model. We conducted a psychological network analysis to exploratively study the relationships between the model’s different factors and tested the assumptions of the CBM by evaluating a structural equation model (SEM) that incorporated all factors of the model.

Results

Network analyses revealed clustering in our data: Health anxiety and different cognitive factors are closely related, whereas somatic symptoms and state negative affectivity are strongly associated. Our SEM showed adequate fit.

Conclusions

Our findings from an exploratory and a confirmatory approach give empirical support for the CBM, suggesting it as a suitable model to explain bodily symptoms in the general population and to possibly guide clinical practice. The network model additionally indicates the necessity to apply an individualized CBM for patients, depending on a preponderance of either persistent somatic symptoms or health concerns.
Evaluation of the Pulmonary Arteries on CTPA With Dual Energy CT
Authors: Gliner-Ron Masha , Sosna Jacob , Leichter Isaac , Goldberg S. Nahum , Shaham Dorit , Cohen Dotan , Malul Yehuda , Romman Zimam , Lev-Cohain Naama
Published: April 2024

Purpose:

To perform qualitative and quantitative evaluation of low-monoenergetic images (50 KeV) compared with conventional images (120 kVp) in pulmonary embolism (PE) studies and to determine the extent and clinical relevance of these differences as well as radiologists’ preferences.

Materials and Methods:

One hundred fifty CT examinations for PE detection conducted on a single-source dual-energy CT were retrospectively evaluated. Attenuation, contrast-to-noise-ratio, and signal-to-noise-ratio were obtained in a total of 8 individual pulmonary arteries on each exam—including both central (450/1200=37.5%) and peripheral (750/1200=62.5%) locations. Results were compared between the conventional and low-monoenergetic images. For quality assessment, 41 images containing PE were presented side-by-side as pairs of slices in both conventional and monoenergetic modes and evaluated for ease in embolus detection by 9 radiologists: cardiothoracic specialists (3), noncardiothoracic specialists (3), and residents (3). Paired samples t tests, a-parametric Wilcoxon test, McNemar test, and kappa statistics were performed.

Results:

Monoenergetic images had an overall statistically significant increased average ratio of 2.09 to 2.26 (P<0.05) for each measured vessel attenuation, with an increase in signal-to-noise ratio (23.82±9.29 vs. 11.39±3.2) and contrast-to-noise ratio (17.17±6.7 vs 7.27±2.52) (P<0.05). Moreover, 10/150 (6%) of central pulmonary artery measurements considered suboptimal on conventional mode were considered diagnostic on the monoenergetic images (181±14.6 vs. 387.7±72.4 HU respectively, P<0.05). In the subjective evaluation, noncardiothoracic radiologists showed a preference towards low-monoenergetic images, whereas cardiothoracic radiologists did not (74.4% vs. 57.7%, respectively, P<0.05).

Conclusions:

The SNR and CNR increase on monoenergetic images may have clinical significance particularly in the setting of sub-optimal PE studies. Noncardiothoracic radiologists and residents prefer low monoenergetic images.
Differentiation Between Invasive Adenocarcinoma and Focal Interstitial Fibrosis among Persistent Pulmonary Part-solid Nodules
Authors: Woo Jung Han , Kim Jong Hee , Jeong Dong Young , Park Sung Goo , Jung Moonki , Kim Chu Hyun , Lee Junghee , Kim Hong Kwan , Han Joungho , Kim Tae Jung , Chung Myung Jin , Cha Yoon Ki
Published: April 2024

Purpose:

Focal interstitial fibrosis (FIF) manifesting as a persistent part-solid nodule (PSN) has been mistakenly treated surgically due to similar imaging features to invasive adenocarcinoma (ADC). The purpose of this study was to observe predictive imaging features correlated with FIF through CT morphologic analysis.

Materials and Methods:

From January 2009 to December 2020, 44 patients with surgically proven FIF in a single institution were enrolled and compared with 88 ADC patients through propensity score matching. Patient characteristics and CT morphologic analysis of persistent PSNs were used to identify predictive imaging features of FIF. Receiver operating characteristic (ROC) curve analysis was used to quantify the performance of imaging features.

Results:

A total of 132 patients with 132 PSNs (44 FIF, 88 ADC; mean age, 67.7±7.58; 75 females) were involved in our analysis. Multivariable analysis demonstrated that preserved peritumoral vascular margin (preserved vascular margin), preserved secondary pulmonary lobule margin (preserved lobular margin), and lower coronal to axial ratio (C/A ratio; cutoff: 1.005) were significant independent predictors of FIF (P<0.05). ROC curve analysis to evaluate the predictive value of the logistic model based on the imaging features of FIF, and the AUC value was 0.881.

Conclusion:

CT imaging features of preserved vascular margin, preserved lobular margin, and lower C/A ratio (cutoff, <1.005) might be helpful imaging features in discriminating FIF over ADC among persistent PSN in clinical practice.
A Study on the Nonsurgical Correction Treatment Age Window and Long-Term Follow-Up of Infants With Congenital Ear Anomalies in China
Authors: Lv Mengshuang , Liu Yujie , Chen Peiwei , Zhu Jikai , Qiu Wenxi , Wang Danni , Zhao Shouqin
Published: April 2024

Objectives:

To evaluate the efficacy of ear molding across various initial ages and analyze challenges encountered by infants beyond the optimal treatment age window.

Methods:

A retrospective review of 331 infants (527 ears) treated with EarWell was conducted over 5 years from January 2017 to March 2022 at a single center. The treatment duration of the ear molding, success rate, recurrence rate, and complication rate were analyzed among the 3 age groups. Concentrate on evaluating treatment outcomes for infants with an initial age exceeding 42 days.

Results:

The mean age at initial treatment was 25±28 days. In addition, it includes a child with cryptotia who is 3.5 years old (1278 d). The mean duration of treatment was 7±5 weeks. In the long-term follow-up, the overall treatment success rate was 92%, with 467 ears (88.6%) showing improvement without recurrence, 30 ears (5.7%) experiencing varying degrees of recurrence, and 30 ears (5.7%) showing no improvement or complete recurrence. A total of 20 infants (3%) developed mild skin complications during treatment.

Conclusions:

Ear molding is a safe and effective option for the treatment of congenital ear anomalies, with a low recurrence rate during long-term follow-up. For infants with congenital auricular anomalies aged over 42 days, ear molding remains a viable option. Treatment success may be influenced by the age at treatment, the subtype of anomalies, and relies on the assessment of a specialized otologist, expert procedural techniques, as well as thorough understanding and cooperation from parents.
Research progress of curcumin in the treatment of sepsis
Authors: Tao Huiping , Shen Lihan
Published: April 2024

Sepsis is a life-threatening organ dysfunction caused by an unregulated host response to infection. It is an important clinical problem in acute and critical care. In recent years, with the increasing research on the epidemiology, and pathogenesis, diagnostic and therapeutic strategies of sepsis, great progress has been made in clinical practice, but there is still a lack of specific and effective treatment plans. Curcuma longa, a leafy plant of the ginger family, which is a common and safe compound, has multiple pharmacological actions, including, but not limited to, scavenging of oxygen free radicals, attenuation of inflammatory response, and anti-fibrotic effects. Great progress has been made in the study of sepsis-associated rodent models and in vitro cellular models. However, the evidence of curcumin in the clinical management practice of sepsis is still insufficient; hence, it is very important to systematically summarize the study of curcumin and sepsis pathogenesis.
INFLUENCES OF HEAT STRESS ON GLUTAMATE TRANSMISSION-DEPENDENT EXPRESSION LEVELS OF IL-1β and IL-18 IN BV-2 MICROGLIAL CELLS
Authors: Chen Er , Zhang Zhi-qiang , Xu An-cong , Huang Fan , He Yan-xuan , Yu Xi-chong , He Guo-xin
Published: April 2024

Objective: This study aimed to explore the impact of heat stress (HS) on glutamate transmission-dependent expression levels of interleukin-1β (IL-1β) and IL-18 in BV-2 microglial cells. Methods: BV-2 microglial cells were cultured in vitro, with cells maintained at 37°C serving as the control. The HS group experienced incubation at 40°C for 1 h, followed by further culturing at 37°C for 6 or 12 h. The experimental group was preincubated with glutamate, the glutamate antagonist riluzole, or the mGluR5 agonist, 2-chloro-5-hydroxyphenylglycine (CHPG), before HS. Glutamate content in BV-2 culture supernatant was assessed using colorimetric assay. Moreover, mRNA expression levels of EAAT3 and/or mGluR5 in BV-2 cells were determined via quantitative polymerase chain reaction. Interleukins (IL-1β and IL-18) in cell culture supernatant were measured using enzyme-linked immunosorbent assay. Western blot analysis was employed to assess protein levels of IL-1β and IL-18 in BV-2 cells. Results: HS induced a significant release of glutamate and increased the expression levels of mGluR5 and EAAT3 in BV-2 cells. It also triggered the expression levels and release of proinflammatory factors, such as IL-1β and IL-18, synergizing with the effects of glutamate treatment. Preincubation with both riluzole and CHPG significantly reduced HS-induced glutamate release and mitigated the increased expression levels and release of IL-1β and IL-18 induced by HS. Conclusion: The findings confirmed that microglia could be involved in HS primarily through glutamate metabolisms, influencing the expression levels and release of IL-1β and IL-18.
Mechanisms of autoimmune encephalitis
Authors: Papi Claudia , Milano Chiara , Spatola Marianna
Published: April 2024

Purpose of review

To provide an overview of the pathogenic mechanisms involved in autoimmune encephalitides mediated by antibodies against neuronal surface antigens, with a focus on NMDAR and LGI1 encephalitis.

Recent findings

In antibody-mediated encephalitides, binding of IgG antibodies to neuronal surface antigens results in different pathogenic effects depending on the type of antibody, IgG subclass and epitope specificity. NMDAR IgG1 antibodies cause crosslinking and internalization of the target, synaptic and brain circuitry alterations, as well as alterations of NMDAR expressing oligodendrocytes, suggesting a link with white matter lesions observed in MRI studies. LGI1 IgG4 antibodies, instead, induce neuronal dysfunction by disrupting the interaction with cognate proteins and altering AMPAR-mediated signaling. In-vitro findings have been corroborated by memory and behavioral changes in animal models obtained by passive transfer of patients’ antibodies or active immunization. These models have been fundamental to identify targets for innovative therapeutic strategies, aimed at counteracting or preventing antibody effects, such as the use of soluble ephrin-B2, NMDAR modulators (e.g., pregnenolone, SGE-301) or chimeric autoantibody receptor T cells (CAART) in models of NMDAR encephalitis.

A deep understanding of the pathogenic mechanisms underlying antibody-mediated encephalitides is crucial for the development of new therapeutic approaches targeting brain autoimmunity.
Gas and Bloat in Female Patients after Antireflux Procedures: Analysis of 934 Cases
Authors: Zimmermann Christopher J , Kuchta Kristine , Amundson Julia R , VanDruff Vanessa N , Joseph Stephanie , Che Simon , Hedberg H Mason , Ujiki Michael B
Published: April 2024

BACKGROUND:

Antireflux procedures (ARPs) are effective treatments for GERD. However, variation in objective and patient-reported outcomes persists. Limited evidence and anecdotal experience suggest that patient sex may play a role. The objective of this study was to compare outcomes after ARPs between male and female patients.

STUDY DESIGN:

We performed a retrospective review of a prospectively maintained database at a single institution. All patients who underwent an ARP for GERD were included. Demographic, clinical, and patient-reported outcomes data (GERD health-related quality of life [HRQL] and reflux symptom index), and radiographic hernia recurrence were collected and stratified by sex. Univariable and multivariable logistic and mixed-effects linear regression were used to control for confounding effects.

RESULTS:

Between 2009 and 2022, 934 patients (291 men and 643 women) underwent an ARP. Reflux symptom index, GERD-HRQL, and gas and bloat scores improved uniformly for both sexes, though female patients were more likely to have higher gas and bloat scores 1 year postprocedure (mean ± SD 1.7 ± 1.4 vs 1.4 ± 1.3, p = 0.03) and higher GERD-HRQL scores 2 years postprocedure (6.3 ± 8.1 vs 4.7 ± 6.8, p = 0.04). Higher gas and bloat scores in women persisted on regression controlling for confounders. Hernia recurrence rate was low (85 patients, 9%) and was similar for both sexes. A final intraprocedural distensibility index 3 mm2/mmHg or more was significantly associated with a 7 times higher rate of recurrence (95% CI 1.62 to 31.22, p = 0.01).

CONCLUSIONS:

Although patients of either sex experience symptom improvement and low rate of recurrence after ARPs, women are more likely to endorse gas and bloat compared with men. Final distensibility index 3 mm2/mmHg or more carries a high risk of recurrence. These results may augment how physicians prognosticate during consultation and tailor their treatment in patients with GERD.
Patency, assessment, and management of central catheter occlusion in adult patients in the intensive care unit: a best practice implementation project
Authors: Irigoyen Paula Marqués , Jimenez Marina Gallego , Arellano Eva María López , Pérez Montserrat Sicilia , Cabredo Rebeca Villanueva
Published: April 2024

Introduction:

Cannulation with a central venous catheter (CVC) is a common procedure used in critical care. One of the main complications is occlusion, which can lead to delayed treatment, prolonged hospital stay, and increased health care costs.

Objective:

The aim of this project was to promote evidence-based practice for nurses caring for patients with a CVC in a Spanish intensive care unit. The project also aimed to reduce CVC occlusion and ensure CVC patency.

Methods:

This project was guided by the JBI Model of Evidence-based Healthcare and the JBI Evidence Implementation Framework. Seven phases were followed using evidence-based auditing and feedback. The JBI Practical Application of Clinical Evidence System (PACES) and Getting Research into Practice (GRiP) tools were used to support data collection, data analysis, and implementation planning.

Results:

After project implementation, the following results were obtained. Criterion 1 (assessing the CVC, flushing, and aspirating) reached 100% compliance in both audits. Criterion 2 (occlusion documentation) showed a modest improvement, rising from 13.33% to 36.67%. Improvement for Criterion 3 (the need for a policy and protocol) was excellent, rising from 0% at baseline to 100% following implementation. Criterion 4 (rapid instillation of an appropriate thrombolytic agent if a CVC is occluded) remained at 0% compliance in both audits. Criterion 5 (continuing education for health care professionals) improved from 10% to 60%. Criterion 6 (flushing and locking before procedures) improved from 90% to 100%.

Conclusion:

The project objectives were largely met and resulted in a protocol, which has been shared with other departments within the hospital. The implementation of best clinical practice will be continued, including the use of thrombolytic agents.

Spanish abstract:

http://links.lww.com/IJEBH/A200
Paraburkholderia translucens sp. nov. and Paraburkholderia sejongensis sp. nov., isolated from grassland soil and showing plant growth promoting potential
Authors: Oh Eun Tak , Ra Jun Sik , Kim Seung Bum
Published: April 2024

Two Gram-negative bacterial strains designated MMS20-SJTN17T and MMS20-SJTR3T were isolated from a grassland soil sample, and taxonomically characterized using a polyphasic approach. The 16S rRNA gene sequence analysis indicates that both strains belong to the genus Paraburkholderia of the class Betaproteobacteria, with strain MMS20-SJTN17T being mostly related to Paraburkholderia sprentiae WSM5005T (96.45 % sequence similarity) and strain MMS20-SJTR3T to Paraburkholderia tuberum STM678T (98.59 % sequence similarity). MMS20-SJTN17T could grow at 15–40 °C (optimum, 25–30 °C) and at pH 6.0–8.0 (optimum, pH 6.0–7.0), whereas MMS20-SJTR3T could grow at 10–40 °C (optimum, 30–37 °C) and at pH 6.0–8.0 (optimum, pH 6.0). Both strains tolerated up to 1 % (w/v) NaCl (optimum, 0 %). The major fatty acids of MMS20-SJTN17T were C16 : 0 and C19 : 0 cyclo ω8c, and those of MMS20-SJTR3T were C17 : 0 cyclo and a summed feature comprising C18 : 1 ω7c and/or C18 : 1 ω6c. The major isoprenoid quinone of both strains was ubiquinone-8 and the diagnostic polar lipids were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. Regarding plant growth promoting potential, both strains were capable of producing indole acetic acid, siderophore and 1-aminocyclopropane-1-carboxylic acid deaminase, and also showed phosphate-solubilizing activity. A genome-based comparison using orthologous average nucleotide identity and digital DNA–DNA hybridization values indicates that strain MMS20-SJTN17T shares highest relatedness with Paraburkholderia monticola JC2948T and MMS20-SJTR3T with Paraburkholderia antibiotica G-4-1-8T, with values clearly below the cutoffs for species distinction. Examination of biosynthetic gene clusters responsible for secondary metabolite production reveals unique characteristics distinguishing each strain from closely related Paraburkholderia species. On the basis of genotypic, phenotypic, chemotaxonomic and phylogenomic data, each strain should be classified as a novel species of the genus Paraburkholderia, for which the names Paraburkholderia translucens sp. nov. (=MMS20-SJTN17T=LMG 32366T=KCTC 82783T) and Paraburkholderia sejongensis sp. nov. (=MMS20-SJTR3T=LMG 32367T=KCTC 82784T) are proposed.
Differences in HIV-1 reservoir size, landscape characteristics and decay dynamics in acute and chronic treated HIV-1 Clade C infection
Authors: Reddy Kavidha , Lee Guinevere Q. , Reddy Nicole , Chikowore Tatenda J.B. , Baisley Kathy , Dong Krista L. , Walker Bruce D. , Yu Xu G. , Lichterfeld Mathias , Ndung’u Thumbi
Published: April 2024

Background

Persisting HIV reservoir viruses in resting CD4 T cells and other cellular subsets are the main barrier to cure efforts. Antiretroviral therapy (ART) intensification by early initiation has been shown to enable post-treatment viral control in some cases but the underlying mechanisms are not fully understood. We hypothesized that ART initiated during the hyperacute phase of infection before peak will affect the size, decay dynamics and landscape characteristics of HIV-1 subtype C viral reservoirs.

Methods

We studied 35 women at high risk of infection from Durban, South Africa identified with hyperacute HIV infection by twice weekly testing for plasma HIV-1 RNA. Study participants included 11 who started ART at a median of 456 (297-1203) days post onset of viremia (DPOV), and 24 who started ART at a median of 1 (1-3) DPOV. We used peripheral blood mononuclear cells (PBMC) to measure total HIV-1 DNA by ddPCR and to sequence reservoir viral genomes by full length individual proviral sequencing (FLIP-seq) from onset of detection of HIV up to 1 year post treatment initiation.

Results

Whereas ART in hyperacute infection blunted peak viremia compared to untreated individuals (p<0.0001), there was no difference in total HIV-1 DNA measured contemporaneously (p=0.104). There was a steady decline of total HIV DNA in early treated persons over 1 year of ART (p=0.0004), with no significant change observed in the late treated group. Total HIV-1 DNA after one year of treatment was lower in the early treated compared to the late treated group (p=0.02). Generation of 697 single viral genome sequences revealed a difference in the longitudinal proviral genetic landscape over one year between untreated, late treated, and early treated infection: the relative contribution of intact genomes to the total pool of HIV-1 DNA after 1 year was higher in untreated infection (31%) compared to late treated (14%) and early treated infection (0%). Treatment initiated in both late and early infection resulted in a more rapid decay of intact (13% and 51% per month) versus defective (2% and 35% per month) viral genomes. However, intact genomes were still observed one year post chronic treatment initiation in contrast to early treatment where intact genomes were no longer detectable. Moreover, early ART reduced phylogenetic diversity of intact genomes and limited the seeding and persistence of cytotoxic T lymphocyte immune escape variants in the reservoir.

Conclusions

Overall, our results show that whereas ART initiated in hyperacute HIV-1 subtype C infection did not impact reservoir seeding, it was nevertheless associated with more rapid decay of intact viral genomes, decreased genetic complexity and immune escape in reservoirs, which could accelerate reservoir clearance when combined with other interventional strategies.
Streptococcus pneumoniaeinfection of lung epithelial cells induces internalization of surface GPI-anchored proteins through pneumolysin-mediated activation of host Rho GTPases
Authors: Lee Nick , Bhalla Manmeet , Pereira Joana M. , Clark Stacie , Roggensack Sara E. , Lovy Alenka , Pereira Michael J. , Arroyo Guillermo , Adams Walter , Camilli Andrew , Tweten Rodney K. , Leong John M. , Sousa Sandra , Bou Ghanem Elsa N.
Published: April 2024

A return to homeostasis after infection-associated cellular injury can be accelerated by a rapid damage response.S. pneumoniae, a typically asymptomatic colonizer of the host upper respiratory tract, can cause serious and life-threatening infections when it gains access to the lungs and other organs. The cholesterol bindingS. pneumoniaepore-forming toxin, pneumolysin (PLY), is central to the induction of host cell damage. Here, we first found that mouse lung infection byS. pneumoniaediminished pulmonary expression of CD73, a glycosylphosphatidylinositol anchored protein (GPI-AP) that modulates inflammation. Infection of the human pulmonary epithelial cell line H292 resulted in a PLY-dependent reduction of not only cell surface CD73, but also the population of surface expressed GPI-APs. The decrease in cell surface GPI-APs was rapid, required pore-forming activity, and could be recapitulated by purified PLY and other cholesterol binding cytolysins. In response to PLY-mediated insult, GPI-APs were not released from the surface of epithelial cells in extracellular vesicles but rather internalized by a mechanism dependent on the Rho GTPases RhoA and Cdc42. Internalization of GPI-APs was associated with lower levels of PLY-induced apoptosis and membrane permeabilization. These findings suggest that internalization of GPI-APs from epithelial cell membranes may constitute a rapid innate repair response to cell damage induced by PLY and other pore forming toxins that could help bacteria evade host defenses as many GPI-APs have roles in immunity.

Author summary

Streptococcus pneumoniaecauses serious infections that can result in mortality. The pore- forming toxin, pneumolysin (PLY) produced by these bacteria is important for their ability to cause disease. Understanding how the host responds to damage by this toxin can result in better treatment against infection. In this study, we found that PLY-mediated injury results in decreased expression of glycosylphosphatidylinositol anchored proteins (GPI-AP) from the cell surface by internalization. GPI-AP co-localize in cholesterol-rich areas of the membrane where PLY inserts to form pores and cells with decreased surface GPI-APs were associated with less of PLY-induced cell death and membrane permeabilization. These results suggest that GPI-AP are internalized as part of repair mechanisms activated in response to infection-induced cell injury. As many GPI-APs have important roles in the immune response, their removal from the cell may inadvertently help the bacteria establish better infection.
Minimally and vaguely informative priors to combat practical parameter non-identifiability of hidden Markov models exemplified by ion channel data
Authors: Münch Jan L. , Schmauder Ralf , Paul Fabian , Habeck Michael
Published: April 2024

Abstract

Hidden Markov Model (HMM) inference for time-series data from ion channels or other biomolecules is challenging. We argue that inference on partially observed chemical reaction networks (CRNs) suffers from practical parameter non-identifiability (non-PI) that often goes unnoticed in maximum likelihood (ML) inferences. Limitations in the signal bandwidth and a poor signal-to-noise ratio only add to the non-PI problem. We study the role of the prior distribution in the face of non-PI. In particular, we advocate using minimally informative (MI) priors and additional restrictions on the parameter space that can be derived from physical considerations. Using patch clamp (PC) ion-channel measurements as a prototypical time series, we demonstrate Bayesian strategies for alleviating non-PI problems with sharpened prior information.

In Bayesian statistics, the prior can substantially modulate the posterior. We demonstrate that non-PI can be severely harmful when using uniform priors on the rate matrix of HMMs, which are implicitly assumed in ML. We show that MI priors enable meaningful HMM inference with data whose quality can be one to two orders of magnitude worse than required to reach the same accuracy with uniform priors. However, we also demonstrate that non-PI pathologies can persist even with a prior MI. In this case, the MI prior alleviates but does not entirely resolve the problem of improper posteriors. For complex HMMs, stronger prior assumptions are needed to render the posterior proper.

We propose to confine the parameters to a sampling box whose limits are physically reasonable and derived from theory. This fusion of data and physical information allows for meaningful inferences even for the most complex HMM with data of the lowest quality that we tested. However, hard theoretical limits, such as diffusion-limited binding rates, are rarely available. As an alternative, we test a vague prior on the ratios of each pair of binding rates and additionally unbinding rates, thereby softly linking them. This implicitly assumes finite cooperativity and introduces a bias towards non-cooperativity. However, in contrast to the standard practice of choosing equal chemical rates, which supposes strict non-cooperativity, this additional prior still allows for cooperativity. Despite its vagueness, our prior renders the posterior either proper in a strict sense orsufficientlyproper for all data sets we considered without imposing the assumption of non-cooperativity. Hence, our approach can infer how likely different degrees of cooperativity are. Combining theoretical upper limits and vague finite cooperativity assumptions dramatically improves inferences.
SonoNERFs: Neural Radiance Fields applied to Biological Echolocation Systems allow 3D Scene Reconstruction Through Perceptual Prediction
Authors: Jansen Wouter , Steckel Jan
Published: April 2024

In this paper, we introduce SonoNERFs, a novel approach that adapts Neural Radiance Fields (NeRFs) to model and understand the echolocation process in bats, focusing on the challenges posed by acoustic data interpretation without phase information. Leveraging insights from the field of optical NeRFs, our model, termed SonoNERF, represents the acoustic environment through Neural Reflectivity Fields. This model allows us to reconstruct three-dimensional scenes from echolocation data, obtained by simulating how bats perceive their surroundings through sound. By integrating concepts from biological echolocation and modern computational models, we demonstrate the SonoNERF’s ability to predict echo spectrograms for unseen echolocation poses and effectively reconstruct a mesh-based and energy-based representation of complex scenes. Our work bridges a gap in understanding biological echolocation and proposes a methodological framework that provides a first order model on how scene understanding might arise in echolocating animals. We demonstrate the efficacy of the SonoNERF model on three scenes of increasing complexity, including some biologically relevant prey-predator interactions.
Cellular and molecular changes in the human osteoarthritic and aging hip pulvinar
Authors: Tilouche Bahaeddine , Farhat Stephanie , Short Spencer , Somyk Mariya , Beaulé Paul , Carsen Sasha , Grammatopoulos George , Coutu Daniel L.
Published: April 2024

Osteoarthritis (OA) represents a multifaceted pathology characterized by intricate signaling across various joint tissues, where the sub-synovial adipose tissue (ssAT) has been suggested to play diverse roles, from serving as a stem cell reservoir, mechanosensing, serving as a neuroendocrine organ, to modulating inflammation. In this study, we aimed to uncouple the cellular and molecular alterations within the human hip ssAT (the pulvinar) linked to OA and aging, elucidating the distinct contributions of disease onset and progression versus normal aging. Our findings show a pronounced increase in mesenchymal stem/progenitor cells (MSPCs) in the osteoarthritic pulvinar, associated with the upregulation of putative MSPC markers (DPP4, and THY1), indicating an adaptive repair response. Concurrently, in OA patients we observed an altered immune landscape featuring reduced innate immune cells and elevated exhausted CD8+ cells, along with upregulation of genes critical for inflammation and fibroblast activation. Our findings reveal a nuanced picture of OA, where increased stem cell numbers and vascularization, combined with specific gene expression patterns differentiate OA from normal aging. This study not only delineates the roles of inflammation, immune regulation, and stem cell activity in the OA pulvinar but also identifies potential therapeutic targets to modulate these pathways, offering novel insights into OA as a complex interplay of degenerative and intrinsic tissue repair.
Imbalance and Composition Correction Ensemble Learning Framework (ICCELF): A novel framework for automated scRNA-seq cell type annotation
Authors: Cui Saishi , Nassiri Sina , Zakeri Issa
Published: April 2024

Single-cell RNA sequencing (scRNA-seq) has gained broad utility and success in revealing novel biological insight in preclinical and clinical investigations. Cell type annotation remains a key analysis task with great influence on downstream interpretation of scRNA-seq data. Traditional machine learning approaches proposed for automated cell type annotation often overlook the inherent imbalance of cell type proportions within biological samples, and the compositional nature of sequencing-based gene expression quantification. In this study, we highlight the importance of accounting for cell type imbalance and compositionality of sequencing count data, and introduce the Imbalance and Composition Corrected Ensemble Learning Framework (ICCELF) as a novel approach to automated cell type annotation. We show via comprehensive evaluation on both simulated and real-world scRNA-seq data that by effectively addressing class imbalance and data compositionality. ICCELF offers a robust and efficient solution that facilitates accurate and reliable cell type annotation, paving the way for enhanced biological discoveries.
Variability of Auditory Brainstem Responses in Diversity Outbred Mice
Authors: Taszus Roxana , Rio Joaquin del , Stoessel Alexander , Nowotny Manuela
Published: April 2024

Inbred mouse strains are mainly used in hearing research as animal models. Most of these lab mice strains consist of genetically identical individuals and natural variability as it is found in wild populations is not represented. Jackson Laboratories generated a new mice strain by an outbred of different mice strains to create mice with different pheno- and genotype, the Diversity Outbred strain (J:DO). By using 20 J:DO mice at the age of eight to nine weeks, we aimed to test the hearing variability in auditory thresholds and measured auditory brainstem responses at 15 different frequencies and sound pressure level from 0 to 80 dB SPL. Our measurements revealed a wide hearing bandwidth in J:DO mice that span over about 4.5 octaves. The high-frequency cut-off of the hearing threshold varied from 21 to 80 kHz and was on median at 64 kHz. Whereas the low frequency cut-off was at 3 kHz with low variation. The median characteristic frequency was found at 15 kHz and showed not a high variation in the sound level to induce an ABR threshold (20 dB SPL). We found not differences in hearing between male and female J:DOs. Future studies on hearing impairments in mice that aim to base on a genetically variable population could benefit from this new mouse strain and use our dataset on the hearing threshold in J:DO mice is a basis.
Connectomic Analysis of Mitochondria in the Central Brain ofDrosophila
Authors: Rivlin Patricia K , Januszewski Michal , Longden Kit D , Neace Erika , Scheffer Louis K , Ordish Christopher , Clements Jody , Phillips Elliott , Smith Natalie , Takemura Satoko , Umayam Lowell , Walsh Claire , Yakal Emily A , Plaza Stephen M , Berg Stuart
Published: April 2024

Mitochondria are an integral part of the metabolism of a neuron. EM images of fly brain volumes, taken for connectomics, contain mitochondria as well as the cells and synapses that have already been reported. Here, from theDrosophilahemibrain dataset, we extract, classify, and measure approximately 6 million mitochondria among roughly 21 thousand neurons of more than 5500 cell types. Each mitochondrion is classified by its appearance - dark and dense, light and sparse, or intermediate - and the location, orientation, and size (in voxels) are annotated. These mitochondria are added to our publicly available data portal, and each synapse is linked to its closest mitochondrion. Using this data, we show quantitative evidence that mitochodrial trafficing extends to the smallest dimensions in neurons. The most basic characteristics of mitochondria - volume, distance from synapses, and color - vary considerably between cell types, and between neurons with different neurotransmitters. We find that polyadic synapses with more post-synaptic densities (PSDs) have closer and larger mitochondria on the pre-synaptic side, but smaller and more distant mitochondria on the PSD side. We note that this relationship breaks down for synapses with only one PSD, suggesting a different role for such synapses.
ADrosophilamodel for mechanistic investigation of tau protein spread
Authors: Bankapalli Kondalarao , Thomas Ruth E. , Vincow Evelyn S. , Milstein Gillian , Fisher Laura V. , Pallanck Leo J.
Published: April 2024

Brain protein aggregates are a hallmark of neurodegenerative disease. Previous work indicates that specific protein components of these aggregates are toxic, including tau in Alzheimer’s disease and related tauopathies. Increasing evidence also indicates that these toxic proteins traffic between cells in a prion-like fashion, thereby spreading pathology from one brain region to another. However, the mechanisms involved in trafficking are poorly understood. We therefore developed a transgenicDrosophilamodel to facilitate rapid evaluation of candidate tau trafficking modifiers. Our model uses the bipartite Q system to drive co-expression of tau and GFP in the fly eye. We find age-dependent tau spread into the brain, represented by detection of tau, but not GFP in the brain. We also found that tau trafficking was attenuated upon inhibition of the endocytic factordynaminor the kinaseglycogen synthase kinase-3β(GSK-3β). Further work revealed that dynamin promotes tau uptake in recipient tissues, whereas GSK-3β appears to promote tau spread via direct phosphorylation of tau. Our robust and flexible system will promote the identification of tau trafficking components involved in the pathogenesis of neurodegenerative diseases.

SUMMARY STATEMENT

The trafficking of toxic proteins in neurodegenerative disease is well-known but poorly understood. Our model will allow rapid and new insight into molecular mechanisms underlying this process.
Resolving and Quantifying Viral-Like Particles via Blind Deconvolution
Authors: Figueroa Jose L , Bellanger Madeline , Fulghum Bryan , Visscher Pieter T , White Richard Allen
Published: April 2024

Viruses represent the most numerous ‘biological entities’ on Earth; but the direct quantification of viruses within ecosystems reminds an ongoing challenge. The classical method of epifluorescence microscopy (EFM) reminds the gold standard measurement of viral-like particles (VLPs) within ecosystems. Quantifying VLPs in epifluorescence microscopy is burdened by ongoing challenges that include manual human counting, an absence of accurate morphological sizing, and the a range of viral sizes (20-300 nm) falling below the diffraction limit of light microscopy. Here, a proof-of-concept computer vision framework for the automated enumeration and sizing of viral-like particles is presented, known as EpiVirQuant. A novel tunable pointspread function is introduced which allows for a dynamic blind deconvolution. Final enumeration by EpiVirQuant was directly compared to manual human counting which yielded 18% more VLPs identified. EpiVirQuant quantified average VLP size of 179.5 nm, which is consistent with median size of VLPs in nature of of _160 nm. Runtime ranged from 60-80 seconds-perimage depending on parameter selection. This provides a viable proof-of-concept cost-effective solution for the enumeration and large-scale morphological analysis of VLPs.
Bi-level Graph Learning Unveils Prognosis-Relevant Tumor Microenvironment Patterns in Breast Multiplexed Digital Pathology
Authors: Wang Zhenzhen , Santa-Maria Cesar A. , Popel Aleksander S. , Sulam Jeremias
Published: April 2024

The tumor microenvironment is widely recognized for its central role in driving cancer progression and influencing prognostic outcomes. There have been increasing efforts dedicated to characterizing this complex and heterogeneous environment, including developing potential prognostic tools by leveraging modern deep learning methods. However, the identification of generalizable data-driven biomarkers has been limited, in part due to the inability to interpret the complex, black-box predictions made by these models. In this study, we introduce a data-driven yet interpretable approach for identifying patterns of cell organizations in the tumor microenvironment that are associated with patient prognoses. Our methodology relies on the construction of a bi-level graph model: (i) a cellular graph, which models the intricate tumor microenvironment, and (ii) a population graph that captures inter-patient similarities, given their respective cellular graphs, by means of a soft Weisfeiler-Lehman subtree kernel. This systematic integration of information across different scales enables us to identify patient subgroups exhibiting unique prognoses while unveiling tumor microenvironment patterns that characterize them. We demonstrate our approach in a cohort of breast cancer patients and show that the identified tumor microenvironment patterns result in a risk stratification system that provides new complementary information with respect to standard stratification systems. Our results, which are validated in two independent cohorts, allow for new insights into the prognostic implications of the breast tumor microenvironment. This methodology could be applied to other cancer types more generally, providing insights into the cellular patterns of organization associated with different outcomes.