bluuebunny/crossref_metadata_2025 huggingface dataset:
The 2024 Pediatric Sepsis Challenge: Predicting In-Hospital Mortality in Children With Suspected Sepsis in Uganda
Authors: Huxford Charly , Rafiei Alireza , Nguyen Vuong , Wiens Matthew O. , Ansermino J. Mark , Kissoon Niranjan , Kumbakumba Elias , Businge Stephen , Komugisha Clare , Tayebwa Mellon , Kabakyenga Jerome , Mugisha Nathan Kenya , Kamaleswaran Rishikesan ,   on behalf of the Pediatric Sepsis Data CoLaboratory
Published: June 2024

The aim of this “Technical Note” is to inform the pediatric critical care data research community about the “2024 Pediatric Sepsis Data Challenge.” This competition aims to facilitate the development of open-source algorithms to predict in-hospital mortality in Ugandan children with sepsis. The challenge is to first develop an algorithm using a synthetic training dataset, which will then be scored according to standard diagnostic testing criteria, and then be evaluated against a nonsynthetic test dataset. The datasets originate from admissions to six hospitals in Uganda (2017–2020) and include 3837 children, 6 to 60 months old, who were confirmed or suspected to have a diagnosis of sepsis. The synthetic dataset was created from a random subset of the original data. The test validation dataset closely resembles the synthetic dataset. The challenge should generate an optimal model for predicting in-hospital mortality. Following external validation, this model could be used to improve the outcomes for children with proven or suspected sepsis in low- and middle-income settings.
Cognitive impact of anticholinergic and sedative burden in people with HIV
Authors: Michael Henry Ukachukwu , Brouillette Marie-Josée , Tamblyn Robyn , Fellows Lesley K. , Mayo Nancy E.
Published: June 2024

Objective:

This study aims to estimate the extent to which anticholinergic and sedative burden is associated with cognitive ability and self-reported cognitive difficulties (SCD) in middle-aged and older adults living with HIV.

Design:

This cross-sectional analysis examined data from the inaugural visit of participants enrolled in the Positive Brain Health Now (BHN) study.

Methods:

Cognitive ability was measured using the Brief Cognitive Ability Measure (B-CAM; higher is better) and SCD using the Perceived Deficits Questionnaire (PDQ; higher is worse). Medication burden was quantified using several scoring systems, including the Anticholinergic Cognitive Burden (ACB), Anticholinergic and Sedative Burden Catalog (ACSBC), Anticholinergic Drug Scale (ADS), Anticholinergic Risk Scale (ARS), and the Sedative Load Model (SLM). Multivariable Ordinary Least Squares and quantile regression were utilized to estimate average effects and distribution-specific impacts, respectively.

Results:

Of 824 participants (mean age 53 years, 84.7% men), 41.4% used anticholinergics (ACSBC) and 39% used sedatives (SLM). High anticholinergic burden was linked to worse cognitive ability [β = −3.81; 95% confidence interval (CI): −7.16, −0.46] and SCD (β = 3.89; 95% CI: 1.08, 6.71). Using three or more anticholinergics worsened cognitive ability (β = −4.45; 95% CI: −8.54, −0.35), and using three or more sedatives increased SCD (β = 4.35; 95% CI: 0.92–7.78). Stronger negative associations were observed in participants with lower cognitive ability and more difficulties.

Conclusions:

These results suggest that anticholinergic and sedative burden may contribute to cognitive impairment in people with HIV. Personalized medication management and regular cognitive assessments could mitigate these adverse effects.
Frequent Cocaine Use is Associated With Larger HIV Latent Reservoir Size
Authors: Aouizerat Bradley E. , Garcia Josephine N. , Domingues Carlos V. , Xu Ke , Quach Bryan C. , Page Grier P. , Konkle-Parker Deborah , Bolivar Hector H. , Lahiri Cecile D. , Golub Elizabeth T. , Cohen Mardge H. , Kassaye Seble G. , DeHovitz Jack , Kuniholm Mark H. , Archin Nancie M. , Tien Phyllis C. , Hancock Dana B. , Johnson Eric Otto
Published: June 2024

Background:

Cocaine—one of the most frequently abused illicit drugs among persons living with HIV [people living with HIV (PLWH)]—slows the decline of viral production after antiretroviral therapy and is associated with higher HIV viral load, more rapid HIV progression, and increased mortality.

Setting:

We examined the impact of cocaine use on the CD4+ T-cell HIV latent reservoir (HLR) in virally suppressed PLWH participating in a national, longitudinal cohort study of the natural and treated history of HIV in the United States.

Methods:

CD4+ T-cell genomic DNA from 434 women of diverse ancestry (ie, 75% Black, 14% Hispanic, 12% White) who self-reported cocaine use (ie, 160 cocaine users, 59 prior users, 215 non-users) was analyzed using the Intact Proviral HIV DNA Assay, measuring intact provirus per 106 CD4+ T cells.

Findings:

HIV latent reservoir size differed by cocaine use (ie, median [interquartile range]: 72 [14–193] for never users, 165 [63–387] for prior users, 184 [28–502] for current users), which was statistically significantly larger in both prior (P = 0.023) and current (P = 0.001) cocaine users compared with never users.

Conclusions:

Cocaine use may contribute to a larger replication competent HLR in CD4+ T cells among virologically suppressed women living with HIV. Our findings are important because women are underrepresented in HIV reservoir studies and in studies of the impact of cocaine use on outcomes among PLWH.
Efficacy of Internet Recruitment and HIV Self-Testing for Diagnosing HIV Infections Among Black and Hispanic/Latino MSM and Transgender Women in 11 US States, 2020–2021
Authors: MacGowan Robin J. , Chavez Pollyanna R. , Dana Ruth , Hannah Marissa , Raiford Jerris L. , Caldwell Joanna A. , Wall Kristin M. , Johnson Jeffrey A. , Sharma Akshay , Hightow-Weidman Lisa , Stephenson Rob , Sanchez Travis , Smith Amanda J. , Sullivan Stephen , Jones Jeb , Sullivan Patrick S.
Published: June 2024

Introduction:

We evaluated internet platforms for distributing HIV self-tests (HIVSTs) to Black or African American (Black) and Hispanic or Latino men who have sex with men (MSM) and transgender women (TGW).

Methods:

We recruited MSM and TGW from general interest, dating, and lesbian, gay, bisexual, and transgender platforms. Two HIVSTs were mailed to all MSM and TGW. Surveys (screening, baseline, 4-month, and results reporting) were completed online. After 4 months, participants were mailed another HIVST and a dried blood spot card. All HIVST interpretations and images of HIVST devices were reported online.

Results:

Of 2093 MSM and 102 TGW, most were recruited through general interest and dating platforms. Over 50% were 18–29 years old, most identified as gay or bisexual. Overall, 45% had not tested for HIV in the past 12 months, and 9.1% of MSM reported a positive (reactive for HIV antibodies) HIVST result, with the highest percentage among Black MSM (11.5%). Dating platforms recruited higher percentages of MSM who recorded positive results compared with MSM from general interest platforms during the intervention period (11.9% vs 5.5% (P < 0.0001)), and MSM who had never tested for HIV reported a greater percentage of positive HIVST results compared with MSM who had been tested for HIV before enrollment (16.1% vs. 7.1%; P < 0.0001). MSM were able to correctly interpret and report HIVST results. Of TGW, 7% reported a positive HIVST result.

Conclusions:

Internet dating and general interest platforms can be key to increasing awareness of infection among BMSM, HMSM, and TGW persons, including those who do not use existing HIV services.

Trial registration:

www.clinicaltrials.gov Identifier: NCT04219878.
Markers of Maternal Bone and Renal Toxicity Through 50 Weeks Postpartum: IMPAACT 2010 (VESTED) Trial
Authors: Masheto Gaerolwe , Brummel Sean S. , Ziemba Lauren , Shepherd John , Mbengeranwa Tapiwa , Igawa Laarni , Coletti Anne , Mukura Dorinda , Rossouw Lindie , Theron Gerhard , Krotje Chelsea , Jean-Philippe Patrick , Chakhtoura Nahida , Cassim Haseena , Mathiba Sisinyana Ruth , Maena Joel , Murtaugh William , Fairlie Lee , Currier Judith , Hoffman Risa , Chinula Lameck , Sax Paul E. , Stranix-Chibanda Lynda , Lockman Shahin ,   for the IMPAACT 2010/VESTED Study Team and Investigators
Published: June 2024

Background:

Safety data from randomized trials of antiretrovirals in pregnancy are scarce. We evaluated maternal bone and renal data from the International Maternal Pediatric Adolescent AIDS Clinical Trials Network 2010 trial, which compared the safety and efficacy of 3 antiretroviral therapy regimens started in pregnancy: dolutegravir + emtricitabine/tenofovir alafenamide (DTG + FTC/TAF), dolutegravir + emtricitabine/tenofovir disoproxil fumarate (DTG + FTC/TDF), and efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF).

Methods:

A subset of participants underwent dual-energy X-ray absorptiometry scans at postpartum week 50 only. Maternal bone mineral density (BMD) Z-scores were compared between arms. Maternal creatinine was measured at enrolment and periodically through week 50 postpartum, and by-arm differences in average weekly change in estimated creatinine clearance were compared.

Results:

Six hundred forty-three participants were randomized to DTG + FTC/TAF (N = 217) or DTG + FTC/TDF (N = 215) or EFV/FTC/TDF (N = 211). Median age = 27 years (IQR 23, 32), median CD4 count = 466 cells/mm3 (IQR 308, 624); 564 (88%) women enrolled in Africa and 479 (74%) breastfed. Week 50 postpartum dual-energy X-ray absorptiometry results from 154 women were included in the analysis. Hip and spine BMD was on average higher in women in the DTG + FTC/TAF and lower in the DTG + FTC/TDF and EFV/FTC/TDF arms, but no significant differences in BMD Z-scores were observed between treatment groups. The weekly rate of change in estimated creatinine clearance differed among treatment groups during the antepartum period, but not over the full study follow-up.

Conclusions:

Markers of bone and renal toxicity did not differ significantly through week 50 postpartum among women randomized to start DTG + FTC/TAF or DTG + FTC/TDF or EFV/FTC/TDF in pregnancy.
Switching to Low Neurotoxic Antiretrovirals to Improve Neurocognition Among People Living With HIV-1-Associated Neurocognitive Disorder: The MARAND-X Randomized Clinical Trial
Authors: Lazzaro Alessandro , Vai Daniela , Barco Ambra , Stroffolini Giacomo , Pirriatore Veronica , Guastamacchia Giulia , Nigra Marco , Ghisetti Valeria , Tettoni Maria Cristina , Noce Giuseppe , Giaccone Claudia , Trunfio Mattia , Trentalange Alice , Bonora Stefano , Di Perri Giovanni , Calcagno Andrea
Published: June 2024

Background:

The pathogenesis of HIV-associated neurocognitive (NC) impairment is multifactorial, and antiretroviral (ARV) neurotoxicity may contribute. However, interventional pharmacological studies are limited.

Methods:

Single-blind, randomized (1:1), controlled trial to assess the change of NC performance (Global Deficit Score, GDS, and domain scores) in PLWH with NC impairment randomized to continue their standard of care treatment or to switch to a less neurotoxic ARV regimen: darunavir/cobicistat, maraviroc, emtricitabine (MARAND-X). Participants had plasma and cerebrospinal fluid HIV RNA< 50 copies/mL, R5-tropic HIV, and were on ARV regimens that did not include efavirenz and darunavir. The change of resting-state electroencephalography was also evaluated. The outcomes were assessed at week 24 of the intervention through tests for longitudinal paired data and mixed-effect models.

Results:

Thirty-eight participants were enrolled and 28 completed the follow-up. Global Deficit Score improved over time but with no difference between arms in longitudinal adjusted models. Perceptual functions improved in the MARAND-X, while long-term memory improved only in participants within the MARAND-X for whom the central nervous system penetration-effectiveness (CNS penetration effectiveness) score increased by ≥3. No significant changes in resting-state electroencephalography were observed.

Conclusions:

In this small but well-controlled study, the use of less neurotoxic ARV showed no major beneficial effect over an unchanged regimen. The beneficial effects on the memory domain of increasing CNS penetration effectiveness score suggest that ARV neuropenetration may have a role in cognitive function.
Relationship of Dose and Signal Enhancement Properties of Gadoquatrane, a New Tetrameric, Macrocyclic Gadolinium-Based Contrast Agent, Compared With Gadobutrol
Authors: Hofmann Birte M. , Riecke Kai , Klein Stefan , Klemens Mark A. , Palkowitsch Petra , Kahn Johannes F. , Posch Helena , Berse Matthias , Ebert Wolfgang
Published: June 2024

Objectives

To investigate the signal-enhancement properties of the tetrameric gadolinium-based contrast agent (GBCA) gadoquatrane in relation to the administered dose and compare its properties to those of a standard dose of gadobutrol, as a representative of the currently established macrocyclic GBCAs for magnetic resonance imaging.

Materials and Methods

In this randomized, single-blind, 4 × 4 crossover study, 43 healthy adults (19–50 years of age) received 3 single IV injections of gadoquatrane (0.01, 0.03, and 0.06 mmol gadolinium/kg body weight) and 1 injection of gadobutrol (0.1 mmol gadolinium/kg body weight) in randomized sequence with 1-week washout periods between administrations. The relative signal enhancement (RSE) was determined in predefined areas of interest in magnetic resonance image sets of the head-neck region. RSE-vs-dose curves (dose-response curves) were established by linear regression, and comparator-equivalent doses were determined by Bayesian inverse regression analysis. Further, 3 blood samples were taken after each injection for pharmacokinetic analyses, and safety data were assessed.

Results

The RSE increased with gadoquatrane dose. A linear function adequately fitted this relationship. In line with the more than 2-fold higher r1 relaxivity of gadoquatrane per gadolinium ion, gadobutrol-equivalent RSE was achieved with gadoquatrane at less than half the gadolinium dose and less than one eighth of the molecule dose.

Administration of gadoquatrane and gadobutrol resulted in very similar dose-normalized gadolinium concentrations in plasma, indicating that the pharmacokinetic profiles are essentially the same. Both contrast agents were well tolerated. Adverse events were rare and not dependent on the dose administered.

Conclusions

Gadoquatrane has the potential to be an effective GBCA that can be used at substantially lower doses in clinical routine than the currently established macrocyclic GBCAs.
Preoperative Surgical or Endoscopic Bile Duct Drainage in Pancreatic Cancer
Authors: Klotz Rosa , Hank Thomas , Berente Miklos P. , Joos Maximilian , Hinz Ulf , Pianka Frank , Kinny-Köster Benedict , Al-Saeedi Mohammed , Strobel Oliver , Hackert Thilo , Schneider Martin , Müller-Stich Beat , Berchtold Christoph , Mehrabi Arianeb , Loos Martin , Büchler Markus W.
Published: June 2024

Background:

Patients with pancreatic cancer and obstructive jaundice routinely undergo endoscopic stent placement (ES). It is well known that ES causes bacterial contamination and infectious complications after pancreatic resection.

Objective:

To compare short-term outcomes and survival in patients undergoing pancreatic head resection after preoperative ES vs preoperative surgical drainage (SD) via T-tube insertion.

Methods:

Patients with obstructive jaundice who underwent SD or ES from 2016 to 2022 were identified from a prospective database. Outcome analyses included microbiological bile contamination, overall morbidity and assessment of the overall complication burden using the Comprehensive Complication Index (CCI). Overall survival was investigated by Kaplan‒Meier analysis.

Results:

A total of 55 patients with SD were identified and matched with 110 ES patients. After the primary intervention, ES patients experienced more complications (ES: 17.3% vs. SD: 3.6%; P=0.013). The overall complication burden after pancreatic resection was higher in ES patients than in SD patients (CCI: 27.2 vs. 19.9; P=0.022). Additionally, bacterial contamination of the bile was more frequent in ES patients compared to SD individuals (94.3% vs. 7.1%; P<0.001) with similar bacteria in 83.3% of postoperative abdominal infections in ES patients. While overall survival did not differ between the two groups, patients with postinterventional complications after ES had an impaired survival compared to those without complications (11.3 mo vs. 20.4 mo; P=0.03).

Conclusion:

SD for obstructive jaundice in resectable pancreatic cancer is associated with a lower overall complication burden. Additionally, patients with complications after ES experience worse overall survival. These findings indicate to rethink our standards of treatment of obstructive jaundice in patients with pancreatic cancer.
The Prognostic Impact of Minimally Invasive Esophagectomy on Survival After Esophagectomy Following a Delayed Interval After Chemoradiotherapy
Authors: Markar Sheraz R. , Sgromo Bruno , Evans Richard , Griffiths Ewen A. , Alfieri Rita , Castoro Carlo , Gronnier Caroline , Gutschow Christian A. , Piessen Guillaume , Capovilla Giovanni , Grimminger Peter P. , Low Donald E. , Gossage James , Gisbertz Suzanne S. , Ruurda Jelle , van Hillegersberg Richard , D’journo Xavier Benoit , Phillips Alexander W. , Rosati Ricardo , Hanna George B. , Maynard Nick , Hofstetter Wayne , Ferri Lorenzo , Berge Henegouwen Mark I. , Owen Richard
Published: June 2024

Objective:

To evaluate prognostic differences between minimally invasive esophagectomy (MIE) and open esophagectomy (OE) in patients with surgery after a prolonged interval (>12 wk) following chemoradiotherapy (CRT).

Background:

Previously, we established that a prolonged interval after CRT before esophagectomy was associated with poorer long-term survival.

Methods:

This was an international multicenter cohort study involving 17 tertiary centers, including patients who received CRT followed by surgery between 2010 and 2020. Patients undergoing MIE were defined as thoracoscopic and laparoscopic approaches.

Results:

A total of 428 patients (145 MIE and 283 OE) had surgery between 12 weeks and 2 years after CRT. Significant differences were observed in American Society of Anesthesiologists grade, radiation dose, clinical T stage, and histologic subtype. There were no significant differences between the groups in age, sex, body mass index, pathologic T or N stage, resection margin status, tumor location, surgical technique, or 90-day mortality. Survival analysis showed MIE was associated with improved survival in univariate (P=0.014), multivariate analysis after adjustment for smoking, T and N stage, and histology (HR=1.69; 95% CI: 1.14–2.5) and propensity-matched analysis (P=0.02). Further subgroup analyses by radiation dose and interval after CRT showed survival advantage for MIE in 40 to 50 Gy dose groups (HR=1.9; 95% CI: 1.2–3.0) and in patients having surgery within 6 months of CRT (HR=1.6; 95% CI: 1.1–2.2).

Conclusions:

MIE was associated with improved overall survival compared with OE in patients with a prolonged interval from CRT to surgery. The mechanism for this observed improvement in survival remains unknown, with potential hypotheses including a reduction in complications and improved functional recovery after MIE.
Effects of Cyclodextrin Curcumin Formulation on Ischemia-Reperfusion Injury in Porcine DCD Liver Transplantation
Authors: Meurisse Nicolas , Wylin Tine , Heedfeld Veerle , Fieuws Steffen , Ceulemans Laurens , Jochmans Ina , Pirenne Jacques , Monbaliu Diethard
Published: June 2024

Background.

Curcumin is a pleiotropic antioxidant polyphenol, which has proven to be highly protective in various models of liver injury and inflammation. We hypothesized that adding a stable aqueous curcumin formulation which comprises a water-soluble cyclodextrin curcumin formulation (CDC) complex of the water-insoluble curcumin molecule (Novobion, Espoo, Finland) to preservation solution during liver procurement may reduce ischemia-reperfusion injury and improve graft function after liver transplantation using donation after circulatory death (DCD).

Methods.

In a preclinical pig model of DCD-liver transplantation, livers exposed to 15’ of warm ischemia were either modulated (N = 6) with a flush of preservation solution (histidine-tryptophan-ketoglutarate) containing CDC (60 µmol/L) through the vena porta and the aorta, or not (controls, N = 6) before 4 h of cold storage. Area under the curve of log serum aspartate aminotransferase, markers of graft function (lactate, glycemia, prothrombin time, and bile production), inflammation (tumor necrosis factor-alpha), and survival were monitored.

Results.

Area under the curve of log serum aspartate aminotransferase were similar between curcumin and control groups (22.12 [20.87–24.88] versus 25.08 [22.1–26.55]; P = 0.28). No difference in the liver function markers were observed between groups except a lower serum lactate level 3-h post-reperfusion in the curcumin group (3 [1.95–6.07] versus 8.2 [4.85–13.45] mmol/L; P = 0.05). Serum tumor necrosis factor-alpha levels were similar in each group. Recipient survival rates were found similar.

Conclusions.

CDC added to the preservation solution in DCD liver pig model did not improve ischemia-reperfusion injury severity, liver function, or survival. Further efforts are needed to explore this strategy, particularly with dynamic preservation, which finds its way into clinical practice.
The Cascade of Care in Management of Solid Organ Transplant Candidates With Latent Tuberculosis Infection
Authors: Chiu Chia-Yu , Mahmood Maryam , Brumble Lisa M. , Vikram Holenarasipur R. , Theel Elitza S. , Beam Elena
Published: June 2024

Background.

Solid organ transplant (SOT) candidates should be screened and treated for latent tuberculosis infection (LTBI) to prevent tuberculosis (TB) reactivation after transplantation. We aimed to assess the steps from positive QuantiFERON (QFT) through LTBI treatment (cascade of care) in the SOT population.

Methods.

We conducted a retrospective study of SOT recipients older than 18 y with a positive QFT during pretransplant evaluation at the Mayo Clinic from January 2010 to June 2023. We analyzed each cascade step to determine associated drop-out factors for LTBI management.

Results.

Of 629 patients who had positive QFT results, 587 (93%) were evaluated by an infectious disease (ID) specialist, 478 (76%) were recommended to start LTBI treatment, 473 (75%) initiated LTBI treatment, and 457 (73%) completed LTBI treatment. LTBI treatment was not recommended in 109 patients evaluated by infectious disease, most of whom had previously received either LTBI (n = 72) or TB (n = 14) treatment. LTBI treatment was initiated before or after transplantation for 45% and 55% of patients, respectively. Isoniazid monotherapy was the most common regimen (92%), and adverse events were rare (7%). Seven patients developed active TB infection posttransplantation under various circumstances (3 without LTBI treatment, 1 during LTBI treatment, and 3 after completing LTBI treatment).

Conclusions.

Our findings demonstrate the variability of LTBI management in SOT recipients with positive QFT. When recommended, most patients completed LTBI treatment successfully. Nonetheless, active TB was noted regardless of whether patients received LTBI treatment. This study highlights the importance of optimizing LTBI management in this population.
The Impact of Donor Body Mass Index on Safety and Outcomes in Living Donor Liver Transplantation: An Analysis of the National United States Database
Authors: Banker Amay , Cywes Claire , Muñoz Nicolas , Taj Raeda , Bittermann Therese , Abt Peter , Abu Gazala Samir
Published: June 2024

Background.

The prevalence of obesity is rising in the general population. Donor obesity (body mass index ≥30 kg/m2) may potentially reduce the donor pool and impact outcomes in living donor liver transplantation (LDLT).

Methods.

We utilized the national transplant database to investigate the impact of donor obesity on donor and recipient outcomes. This was a retrospective cohort study of all LDLTs performed in the United States between January 2010 and June 2023. Outcomes of interest were analyzed by univariable and multivariable logistic regression. Patient and graft survival was evaluated using Kaplan-Meier and Cox proportional analysis.

Results.

Six hundred seventy-four donors with obesity and 3498 donors without obesity were analyzed. Donors with obesity had higher rates of readmission within 1 y of donation (15.9% versus 11.6%; P = 0.003). The risk of readmission was significantly different between 6 wk and 6 mo of donation (8.8% versus 5.9%; P = 0.036). Donor body mass index (odds ratio [OR], 1.460; 95% confidence interval [CI], 1.129-1.999; P = 0.004) and preoperative alkaline phosphatase levels (OR, 1.005; 95% CI, 1.000-1.011; P = 0.038) were independent predictors of donor readmission. High LDLT center volume was associated with reduced odds of donor readmission (OR, 0.509; 95% CI, 0.373-0.694; P < 0.001). Graft and recipient survival was comparable.

Conclusions.

Selection of living donors with obesity may be a potential avenue to increase the available donor pool without compromising recipient outcomes; however, they are at an increased risk for readmission between 6 wk and 6 mo of donation. The reason for readmission requires further study.
Unveiling the mechanisms of black phosphorus nanosheets-induced viable but non-culturable state inBacillus tropicus
Authors: Xiong Zhiqiang , Zhao Qing , Zhao Ming , Liu Liwei , Zeng Jin , Zhang Siyu , Deng Shuo , Liu Daxu , Zhang Xuejiao , Xing Baoshan
Published: June 2024

The release of black phosphorus (BP) nanosheets has raised concerns regarding potential ecological risks. Previous studies have confirmed their toxicity to bacteria, but discrepancies were observed between results obtained from the growth curve and colony forming unit (CFU) methods, indicating the possibility of bacterial cells entering a viable but non-culturable (VBNC) state induced by BP nanosheets. To accurately assess the risks, it is crucial to understand the underlying mechanisms. In this study, we investigated the effect of BP nanosheets onBacillus tropicus, a gram-positive bacterium, using transcriptome sequencing and biological assays. Our findings revealed that BP nanosheets caused minimal cell death but predominately induced the VBNC state in most cells. At the transcriptional level, we observed significant down-regulation of pathways associated with cellular metabolism and respiratory chain in response to BP nanosheet treatment. Bacterial cells in the VBNC state exhibited depressed respiration to maintain basal cellular activity. Additionally, the reduced cellular respiration and metabolic activity were associated with a decrease in antibiotic susceptibility of the bacteria. These results provide new insights into the antibacterial mechanisms of BP nanosheets and emphasize the necessity of employing appropriate approaches, beyond the traditional CFU method, to assess the bacterial toxicity of nanomaterials.

Environmental implication

Bacteria play a crucial role as indicators in ecological risk assessment. Although numerous studies have highlighted the exceptional antibacterial properties of black phosphorus (BP) nanosheets, the unique viable but non-culturable (VBNC) state of bacteria is often overlooked when evaluating the ecological risks of nanomaterial, including BP nanosheets. In our study, we found that BP nanosheets can induceBacillus tropicusinto a VBNC state by suppressing cellular metabolism- and respiratory chain-related pathways, shedding light on their ecological risk assessment implications. This finding underscores the importance of utilizing appropriate approaches in evaluating the bacterial toxicity of nanomaterials.
Hair follicle-resident progenitor cells are a major cellular contributor to heterotopic subcutaneous ossifications in a mouse model of Albright hereditary osteodystrophy
Authors: McMullan Patrick , Maye Peter , Root Sierra H. , Yang Qingfen , Edie Sarah , Rowe David , Kalajzic Ivo , Germain-Lee Emily L.
Published: June 2024

Heterotopic ossifications (HOs) are the pathologic process by which bone inappropriately forms outside of the skeletal system. Despite HOs being a persistent clinical problem in the general population, there are no definitive strategies for their prevention and treatment due to a limited understanding of the cellular and molecular mechanisms contributing to lesion development. One disease in which the development of heterotopic subcutaneous ossifications (SCOs) leads to morbidity is Albright hereditary osteodystrophy (AHO). AHO is caused by heterozygous inactivation ofGNAS, the gene that encodes the α-stimulatory subunit (Gαs) of G proteins. Previously, we had shown using our laboratory’s AHO mouse model that SCOs develop around hair follicles (HFs). Here we show that SCO formation occurs due to inappropriate expansion and differentiation of HF-resident stem cells into osteoblasts. We also show in AHO patients and mice thatSecreted Frizzled Related Protein 2(SFRP2)expression is upregulated in regions of SCO formation and that elimination ofSfrp2in male AHO mice exacerbates SCO development. These studies provide key insights into the cellular and molecular mechanisms contributing to SCO development and have implications for potential therapeutic modalities not only for AHO patients but also for patients suffering from HOs with other etiologies.
IDH1 regulates human erythropoiesis by eliciting chromatin state reprogramming
Authors: Li Mengjia , Zhang Hengchao , Wu Xiuyun , Yu Mengqi , Yang Qianqian , Sun Lei , Li Wei , Jiang Zhongxing , Xue Fumin , Wang Ting , An Xuili , Chen Lixiang
Published: June 2024

Isocitrate dehydrogenase 1 (IDH1) is the key enzyme that was involved in the modulation of cellular metabolism, epigenetic modification and redox states homeostasis. Gain-of-function mutations and decreased expression of IDH1 have been demonstrated to be tightly associated with the pathogenesis of various myeloid malignancies characterized by ineffective erythropoiesis, such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the function and mechanism of IDH1 in human erythropoiesis still remains to be further explored. Here, utilizing the human erythropoiesis system, we present an evidence of IDH1-mediated chromatin state reprogramming besides its well-characterized metabolism effects. We showed that knockdown of IDH1 induced chromatin reorganization and subsequently led to abnormalities of various key biological events in erythroid precursors, which could not be rescued by addition of reactive oxygen species (ROS) scavengers or supplementation of α-ketoglutarate (α-KG). We further revealed that deficiency of IDH1 induces genome-wide changes in distribution and intensity of multiple histone marks, among which H3K79me3 was identified as a critical factor in chromatin state reprogramming. Integrated analysis of ChIP-seq, ATAC-seq and RNA-seq recognized that SIRT1 was the key gene affected by IDH1 deficiency. Thus, our current work provided novel insights for further clarifying fundamental biological function of IDH1 which has substantial implications for an in-depth understanding of pathogenesis of diseases with IDH1 dysfunction and accordingly development of therapeutic strategies.
Next Generation Aging Clock: A Novel Approach to Decoding Human Aging Through Over 3000 Cellular Pathways
Authors: Xiong Jianghui
Published: June 2024

This paper introduces ‘Next Generation Aging Clock Models,’ a new approach aimed at improving disease prediction by defining aging clocks for specific cellular components or pathways, rather than giving a single value for the entire human body. The methodology consists of two stages: a pre-training stage that creates 3,028 generic pathway aging models by integrating genome-wide DNA methylation data with gene ontology and pathway databases, and a fine-tuning stage that produces 30,280 disease-specific pathway aging models using DNA methylation profiles from 3,263 samples across 10 age-related diseases. Our findings show the model’s predictive power for various diseases. For example, the aging index of blood vessel endothelial cell migration can predict Atherosclerosis with an odds ratio of 80. Alzheimer’s disease can be predicted by the aging index of response to DNA damage stimulus, Major Depressive Disorder by the organization of the mitochondrion, breast cancer by DNA repair, and the severity of COVID-19 by neutrophil degranulation, with an odds ratio of 8.5. Additionally, a global analysis revealed that aging-related diseases can be categorized into nucleus aging (such as Alzheimer’s disease) and cytoplasm aging (such as Parkinson’s disease). This model provides a comprehensive view of aging from the organelle to the organ level using just a blood or saliva sample. This innovative approach is expected to be a valuable tool for research into aging-related diseases and for personalized aging interventions.
C->U transition biases in SARS-CoV-2 – still rampant four years from the start of the COVID-19 pandemic
Authors: Simmonds Peter
Published: June 2024

The evolution of SARS-CoV2 in the pandemic and post-pandemic periods has been characterised by rapid adaptive changes that confer immune escape and enhanced human-to-human transmissibility. Sequence change is additionally marked by an excess number of C->U transitions suggested as being due to host-mediated genome editing. To investigate how therse influence the evolutionary trajectory of SARS-CoV-2, 2000 high quality, coding complete genome sequences of SARS-CoV-2 variants collected pre-September, 2020, and from each subsequently appearing alpha, delta, BA.1, BA.2, BA.5, XBB, EG, HK and JN.1 lineages were downloaded from NCBI Virus in April, 2024. C->U transitions were the most common substitution during diversification of SARS-CoV-2 lineages over the 4-year observation period. A net loss of C bases and accumulation of U’s occurred at a constant rate of approximately 0.2%-0.25% / decade. C->U transitions occurred in over a quarter of all sites with a C (26.5%; range 20.0%-37.2%), around 5 times more than observed for the other transitions (5.3%-6.8%). In contrast to an approximately random distribution of other transitions across the genome, most C->U substitutions occurred at statistically preferred sites in each lineage. However, only the most C->U polymorphic sites showed evidence for a preferred 5’U context previously associated with APOBEC 3A editing. There was a similarly weak preference for unpaired bases suggesting much less stringent targeting of RNA than mediated by A3 deaminases in DNA editing. Future functional studies are required to determine editing preferences, impacts on replication fitness in vivo of SARS-CoV-2 and other RNA viruses and impact on host tropism.
Effects of low-dose monacolin K on the circulating proteome in individuals with suboptimal cholesterolaemia: A randomised clinical trial
Authors: Cicero Arrigo F.G. , Uboldi Patrizia , Beretta Giangiacomo , Fogacci Federica , Grandi Elisa , Svecla Monika , Norata Giuseppe Danilo
Published: June 2024

Red yeast rice (RYR) is a traditional Chinese product obtained by fermenting rice with the yeastMonascus purpureusand contains monacolin K, which is chemically identical to lovastatin, a drug with cholesterol-lowering activity. The European Food Safety Authority (EFSA) has evaluated the safety and efficacy of RYR supplements for managing cholesterol levels. In 2018, EFSA published a scientific opinion on the use of monacolin K from RYR in food supplements, concluding that monacolins from RYR may raise significant safety concerns at a use level of 10 mg/ day. Following that, the European Commission declared in 2022 that RYR products must contain less than 3 mg of monacolins for daily consumption. The aim of this work was to perform a comprehensive profiling of plasma markers of muscle and liver dysfunction by extensive untargeted plasma proteomics in healthy volunteers with suboptimal cholesterolaemia who were randomly assigned to receive a dietary supplement containing RYR (total monacolin <3 mg) or placebo for one month.

No changes in classical markers of liver (AST, ALT) or muscle (CPK) function were detected in the plasma samples of patients treated with the supplement compared to placebo. Interestingly, the analysis of circulating proteins marking an early acute response in the liver, such as serum amyloid A4, orosomucoid 2, haptoglobin-related protein, prothrombin, α-1-antitrypsin, α-2-HS- glycoprotein, serum amyloid P (APCS), orosomucoid 1, c-reactive protein (CRP) and α-2- macroglobulin confirmed an overlapping profile in the two groups. Similarly, the analysis of ryanodine receptor 1, titin, dystrophin and myosin 7 again showed a similar profile in the two groups. These data indicate that a low dose of monacolin K (<3 mg/day) in subjects with suboptimal cholesterolaemia does not increase levels of markers of liver and skeletal muscle function in plasma, excluding a deleterious effect of monacolin K on these tissues.
Electrical signaling and coordinated behavior in the closest relative of animals
Authors: Colgren Jeffrey , Burkhardt Pawel
Published: June 2024

The transition between simple to complex multicellularity involves large degrees of division of labor and specialization of cell types. In animals, complex sensory motor systems are primarily built around the fundamental cell types of muscles and neurons, though the evolutionary origin of these cells, and their integration, remains unclear. Here, in order to investigate sensory-behavior coupling in the closest relatives of animals, we established a line of the choanoflagellate,Salpingoeca rosetta, which stably expresses the calcium indicator RGECO1. Using this, we identify a novel cellular behavior associated with electrical signaling, in which ciliary arrest is coupled with apical-basal contraction of the cell. This behavior, and the associated calcium transients, are synchronized in the multicellular state and result in coordinated ciliary arrest and colony wide contraction, suggesting information is spread amongst the cells. Our work reveals fundamental insights into how choanoflagellates sense and respond to their environment and offer a new perspective into the integration of cellular and organism wide behavior in the closest protistan relatives of animals.
Reconstructing Biological Molecules with Help from Video Gamers
Authors: Petrides Andreas C. , Joosten Robbie P. , Players Foldit , Khatib Firas , Horowitz Scott
Published: June 2024

Foldit is a citizen science video game in which players tackle a variety of complex biochemistry puzzles. Here, we describe a new series of puzzles in which Foldit players improve the accuracy of the public repository of experimental protein structure models, the Protein Data Bank (PDB). Analyzing the results of these puzzles showed that the Foldit players were able to considerably improve the deposited structures and thus, in most cases, improved the output of the automated PDB-REDO refinement pipeline. These improved structures are now being hosted at PDB-REDO. These efforts highlight the continued need for the engagement of the lay population in science.
Inflammatory markers in pregnancy – surprisingly stable. Mapping trajectories and drivers in four large cohorts
Authors: Gigase Frederieke A.J. , Suleri Anna , Isaevska Elena , Rommel Anna-Sophie , Boekhorst Myrthe G.B.M. , Dmitrichenko Olga , El Marroun Hanan , Steegers Eric A.P. , Hillegers Manon H.J. , Muetzel Ryan L. , Lieb Whitney , Cecil Charlotte A.M. , Pop Victor , Breen Michael , Bergink Veerle , de Witte Lot D.
Published: June 2024

Adaptations of the immune system throughout gestation have been proposed as important mechanisms regulating successful pregnancy. Dysregulation of the maternal immune system has been associated with adverse maternal and fetal outcomes. To translate findings from mechanistic preclinical studies to human pregnancies, studies of serum immune markers are the mainstay. The design and interpretation of human biomarker studies require additional insights in the trajectories and drivers of peripheral immune markers. The current study mapped maternal inflammatory markers (C-reactive protein (CRP), interleukin (IL)-1β, IL-6, IL-17A, IL-23, interferon-γ) during pregnancy and investigated the impact of demographic, environmental and genetic drivers on maternal inflammatory marker levels in four multi-ethnic and socio-economically diverse population-based cohorts with more than 12,000 pregnant participants. Additionally, pregnancy inflammatory markers were compared to pre-pregnancy levels. Cytokines showed a high correlation with each other, but not with CRP. Inflammatory marker levels showed high variability between individuals, yet high concordance within an individual over time during and pre-pregnancy. Pre-pregnancy body mass index (BMI) explained more than 9.6% of the variance in CRP, but less than 1% of the variance in cytokines. The polygenic score of CRP was the best predictor of variance in CRP (>14.1%). Gestational age and previously identified inflammation drivers, including tobacco use and parity, explained less than 1% of variance in both cytokines and CRP. Our findings corroborate differential underlying regulatory mechanisms of CRP and cytokines and are suggestive of an individual inflammatory marker baseline which is, in part, genetically driven. While prior research has mainly focused on immune marker changes throughout pregnancy, our study suggests that this field could benefit from a focus on intra-individual factors, including metabolic and genetic components.
The BMP2 prodomain promotes dimerization and cleavage of BMP6 homodimers and BMP2/6 heterodimers in vivo
Authors: Chauhan Pooja , Xue Yongqiang , Fisher Allison L. , Kim Hyung-Seok , Babitt Jodie L. , Christian Jan L.
Published: June 2024

Bone morphogenetic protein 2 (BMP2) and BMP6 are key regulators of systemic iron homeostasis. All BMPs are generated as inactive precursor proteins that dimerize and are cleaved to generate the bioactive ligand and inactive prodomain fragments, but nothing is known about how BMP2 or BMP6 homodimeric or heterodimeric precursor proteins are proteolytically activated. Here, we conducted in vitro cleavage assays, which revealed that BMP2 is sequentially cleaved by furin at two sites, initially at a site upstream of the mature ligand, and then at a site adjacent to the ligand domain, while BMP6 is cleaved at a single furin motif. Cleavage of both sites of BMP2 is required to generate fully active BMP2 homodimers when expressed inXenopusembryos or liver endothelial cells, and fully active BMP2/6 heterodimers inXenopus. We analyzed BMP activity inXenopusembryos expressing chimeric proteins consisting of the BMP2 prodomain and BMP6 ligand domain, or vice versa. We show that the prodomain of BMP2 is necessary and sufficient to generate active BMP6 homodimers and BMP2/6 heterodimers, whereas the BMP6 prodomain cannot generate active BMP2 homodimers or BMP2/6 heterodimers. We examined BMP2 and BMP6 homodimeric and heterodimeric ligands generated from native and chimeric precursor proteins expressed inXenopusembryos. Whereas native BMP6 is not cleaved when expressed alone, it is cleaved to generate BMP2/6 heterodimers when co-expressed with BMP2. Furthermore, BMP2-6 chimeras are cleaved to generate BMP6 homodimers. Our findings reveal an important role for the BMP2 prodomain in dimerization and proteolytic activation of BMP6.
Hydrolysis of palm kernel meal fibre using a newly isolatedBacillus subtilisF6 with high mannanase activity
Authors: Ong Wei Li , Chan Kam Lock , Suwanto Antonius , Li Zhi , Ng Kian-Hong , Zhou Kang
Published: June 2024

High fibre content is the main limitation of using mannan-rich palm kernel meal (PKM) in feeding non-ruminant livestock. Microbial fermentation stands out as a cost-effective and environmentally friendly approach for hydrolysing fibre in lignocellulosic biomass. In this study, aBacillus subtilisstrain F6 with high mannanase secretion capability was isolated from an environmental source. Fermentation of PKM using strain F6 resulted in at least a 10% reduction in its neutral detergent fibre content. Notably, the strain exhibited a rapid response to PKM, with significant mannanase activity detected as early as 6 h, enabling fibre hydrolysis within a short fermentation period. Subsequent transcriptome analysis uncovered potential enzymes involved in PKM fibre degradation, and the purified recombinant enzymes were generated to assess their activity on PKM fibre degradation. β-mannanase GmuG demonstrated strong hydrolysis activity of PKM fibre, and its biochemical properties were determined. Overall, the study reported the isolation of aB. subtilisstrain suitable for fibre hydrolysis of mannan-rich biomass, followed by an investigation to identify and characterize the enzyme responsible for fibre degradation.

Graphical abstract
Programmable promoter editing for precise control of transgene expression
Authors: Kabaria Sneha R , Bae Yunbeen , Ehmann Mary E , Beitz Adam M , Lende-Dorn Brittany A , Peterman Emma L , Love Kasey S , Ploessl Deon S , Galloway Kate E
Published: June 2024

Subtle changes in gene expression direct cells to distinct cellular states. Identifying and controlling dosedependent transgenes require tools for precisely titrating expression. To this end, we developed a highly modular, extensible framework called DIAL for building editable promoters that allow for fine-scale, heritable changes in transgene expression. Using DIAL, we increase expression by recombinase-mediated excision of spacers between the binding sites of a synthetic zinc finger transcription factor and the core promoter. By nesting varying numbers and lengths of spacers, DIAL generates a tunable range of unimodal setpoints from a single promoter. Through small-molecule control of transcription factors and recombinases, DIAL supports temporally defined, user-guided control of transgene expression that is extensible to additional transcription factors. Lentiviral delivery of DIAL generates multiple setpoints in primary cells and iPSCs. As promoter editing generates stable states, DIAL setpoints are heritable, facilitating mapping of transgene levels to phenotypes. The DIAL framework opens new opportunities for tailoring transgene expression and improving the predictability and performance of gene circuits across diverse applications.