bluuebunny/crossref_metadata_2025 huggingface dataset:
842. Histoplasmosis : An observational study from northern India in non-HIV population.
Authors: Swain Satish , Sekhar Paul Saurav , Aayilliath Adarsh , Maharatna Sayan , Mohan Lal Bhavesh , Punjadath Sryla , Shareef Imtiyaz , Singh Gagandeep , Xess Immaculata , Soneja Manish , Wig Naveet
Published: November 2023

Background

Globally around 40% of histoplasmosis has been reported in HIV population, with other risk factors being transplant recipients, immunosuppressive agents (steroids, TNF-alpha inhibitors) and extreme of ages. Histoplasmosis in India has mostly been reported from the Gangetic plains (Figure 1).

Methods

This current study was conducted in a tertiary care hospital of northern India between January 1, 2021 and December 31, 2022 to look at the epidemiology, clinical profile and treatment outcome of Histoplasmosis patients in a non-HIV cohort. This was a single centered, observational study. All patients with proven Histoplasmosis (according to EORTC/MSGERC 2019 criteria) were included.

Results

Baseline Characteristics: This study involved 20 patients with a mean age of 52.05 ± 10.87 years with 70% being male. All the patients were from endemic areas of Gangetic belt in India. Majority of the patients (80%) were immunocompetent (Table 1). All cases (100%) were diagnosed on histopathology.

Clinical and Laboratory Characteristics

The common reported complains were fever (75%), weight loss (70%), loss of appetite (75%), skin lesions (25%) and pain abdomen (15%). Mean duration of various symptoms was 3±1.29 months. Hepato-splenomegaly was seen in 45% of cases followed by adrenal involvement (40%), enlarged lymph nodes (35%), skin and oral mucosa involvement (25%) (Figure 2). Out eight patients had who adrenal involvement, five patients (25%) had isolated involvement based on imaging (CT/PET-CT). Cytopenias was seen in upto 75% cases with around 40% had deranged liver functions (Table 2). The most common syndromic diagnosis was progressive disseminated histoplasmosis (PDH) seen in 13 patients with a median age of 49 (30-76) years.

Treatment

13 patients (65%) received induction with Amphotericin B (liposomal) followed by switching to oral itraconazole and 7 patients (35%) got up front itraconazole. At a media follow up of 8 months, 40% of patients had completed treatment and one had patient died.

Conclusion

In a high tuberculosis endemic county like India, Histoplasmosis pose a diagnostic challenge. Although the median time to diagnosis is longer (delay in diagnosis), the overall outcome is good. Majority of our patients were younger immunocompetent individual.

Disclosures

All Authors: No reported disclosures
851. Metabolic Changes Contributing to Age-Associated Antifungal Tolerance in Cryptococcus neoformans
Authors: Yoo Kyungyoon , de Oliveira Natalia Kronbauer , Bhattacharya Somanon , Fries Bettina F
Published: November 2023

Background

Cryptococcus neoformans (CN) is a facultative intracellular pathogen that divides asymmetrically, resulting in different phenotypes of the mother and daughter cells. After 8-10 divisions, mother cells become more resistant to phagocytic killing by macrophages and resistant to antifungals. These resilient traits allow older CN cells to accumulate in the host during chronic infection. Across different pathogenic fungal species, age-associated mitochondrial changes help the cell adapt to various physiological stresses by altering metabolic regulation and ultimately promoting antifungal resistance.

Cryptococcus neoformans is the leading cause of fungal meningitis among immunocompromised populations

Methods

Ten GEN “old” CN cells were obtained by magnetic bead-based isolation and compared to 1-3 GEN “young” cells. Mitochondrial membrane potential, mass, reactive oxygen species (ROS), calcium, and morphology were evaluated by measuring the fluorescence of appropriate cellular dyes and fluorescent microscopy. ATP level was measured by using a kit measuring fluorescence. Lipid droplets and membrane sterols were quantified and visualized by using appropriate cellular dyes. Ergosterol and sphingolipid levels were quantified by a targeted lipidomic approach using LC-MS-MS.

Old mother cells can be separated and isolated by biotinylation and magnetic sorting

Results

Our data demonstrate old CN cells exhibit increased mitochondrial mass, calcium and ROS levels and decreased mitochondrial membrane potential. Additionally, while the mitochondria from young cells show the formation of tubular networks, the mitochondria of old cells exhibit fragmentation. Furthermore, old CN cells have >5-fold higher ATP levels, which can fuel drug efflux pumps. Old cells show more lipid droplets that localize to the vacuole compared to young cells, which can serve as a cellular source of ATP. RT-qPCR analysis and lipidomic studies indicated changes in the synthesis of various ergosterols and sphingolipids, key lipids that are directly linked to pathogenesis and virulence mechanisms in CN.

Metabolic changes in old Cn cells contribute to antifungal tolerance

Conclusion

Our findings suggest that mitochondrial dysfunction of older cells is initially beneficial for CN as it promotes a metabolic switch to fatty acid oxidation and altered regulation of various classes of lipids. Increases in ATP production fuel efflux pumps and the export of azoles. This work furthers our understanding of the “old” CN cell phenotype that emerges during aging.

Disclosures

All Authors: No reported disclosures
856. CT-proET-1 and sFlt-1 as Predictors of Clinical Outcomes in a COVID-19 US Cohort
Authors: Atallah Johnny , Atallah Natalie , Panossian Vahe , Warren Hailey , Inlall Damian , Schwabe Andrej , Johannes Sascha , Wiemer Jan , Mansour Michael
Published: November 2023

Background

Several novel biomarkers have been studied in predicting clinical outcomes in patients with COVID-19. Our study aimed to study C-terminal proendothelin-1 (CT-proET-1) and Soluble fms-like tyrosine kinase-1 (sFlt-1) as predictors of clinical outcomes in a COVID-19 patient cohort from a US-based multicenter trial.

Methods

Data from the Boston Area COVID-19 Consortium (BACC) Bay Tocilizumab Trial was used in this study. Patients with biomarker determinations, and not admitted to the intensive care unit (ICU) on admission, were included. Median concentrations of CT-proET-1 (83.6 pmol/L) and sFlt-1 (81.3 pg/mL) were used as cutoffs in predicting clinical outcomes.

Results

Out of 169 patients, 10.7% mechanically ventilated or dead within 28 days of admission. CT-proET1 concentrations in patients who were mechanically ventilated or dead within 28 days were significantly higher than those who were not (median 119.6 vs 79.1 pmol/L, p=0.001), and higher in patients who were admitted to the ICU during hospitalization compared to those who were not (median 114.5 vs 80.6 pmol/L, p=0.005). Significantly higher sFlt-1 concentrations were seen in patients who were admitted to the ICU compared to those who were not (median 96.0 vs 80.7 pg/mL, p=0.041).

The sensitivity, specificity, PPV and NPV of CT-proET-1 with cutoff 83.6 pmol/L in predicting mechanical ventilation or death were 83%, 54%, 18%, and 96%, respectively, with an AUC of 0.75.

As for the sFlt-1 cutoff of 81.3 pg/mL in predicting mechanical ventilation or death, the sensitivity, specificity, PPV and NPV were 61%, 54%, 14%, and 92%, with an AUC of 0.59.

Conclusion

CT-proET-1 and sFlt-1 function as valuable novel biomarkers in predicting clinical outcomes in COVID-19, with lower levels predicting better outcomes. Further studies are needed to better understand their role in other upper respiratory viral illnesses.

Disclosures

Michael Mansour, MD, PhD, Thermofisher: Grant/Research Support
891. Cytomegalovirus Testing Rates Among Immunocompromised Adults, Adolescents, And Children In The United States
Authors: Jain Purva , Basnet Sandeep , Syed Sahar , Arakaki Brent , Mues Katherine E , Marcum Zachary , Diaz-Decaro John D
Published: November 2023

Background

Cytomegalovirus (CMV) is a latent virus that can cause morbidity and mortality among immunocompromised (IC) individuals. No studies have examined how CMV testing changed throughout the COVID-19 pandemic among IC individuals in the United States (US). This study aimed to estimate CMV testing rates among IC adults (18-94 years), adolescents (12-17 years), and children (0-11 years) during the COVID-19 pandemic.

Methods

This observational cohort study included insured individuals from the US and was conducted using administrative medical and pharmacy claims from HealthVerity from December 2017-May 2022. IC adults, adolescents, and children entered the cohort after 6 months of continuous enrollment and were followed until disenrollment or end of study period. CMV testing was captured using CPT codes (serology and PCR) and was limited to no more than 1 test per day with ≥6 days required between tests. The rate of CMV testing (per 100,000 person-months) was estimated over three time periods defined by key points in the COVID-19 pandemic: pre-COVID-19-era, 06/01/2018-03/31/2020; pre-vaccine-COVID-19-era, 04/01/2020-12/31/2020; and vaccine-COVID-19-era, 01/01/2021-05/31/2022.

Results

The sample included 735,251 IC adults, of whom 4.8% (N=35,391) had ≥1 CMV test over follow-up (median follow-up, 566 days); 12,203 IC adolescents, of whom 15.5% (N=1,896) had ≥1 CMV test over follow-up (median follow-up, 582 days); and 15,854 IC children, of whom 14.7% (N=2,324) had ≥1 CMV test over follow-up (median follow-up, 702 days). The mean rate of CMV tests per 100,000 person-months for IC adults was 1,660 in the pre-COVID-19-era, 1,040 in the pre-vaccine-COVID-19-era, and 983 in the vaccine-COVID-19-era. Similarly, rates of CMV testing declined among IC adolescents and children (adolescents: 7,391 in pre-COVID-19-era, 4,717 in pre-vaccine-COVID-19-era, and 4,219 in vaccine-COVID-19-era; children: 7,556 in pre-COVID-19-era, 4,467 in pre-vaccine-COVID-19-era, and 4,026 in vaccine-COVID-19-era). The highest testing rates were among those with a history of stem cell transplantation in all age cohorts.

Conclusion

CMV test utilization decreased during the COVID-19 pandemic era in the US and remained low through the early COVID-19 vaccine era.

Disclosures

Sandeep Basnet, MD, Moderna Therapeutics: Stocks/Bonds Brent Arakaki, BS, Aetion, Inc.: Employee Katherine E. Mues, PhD, Aetion, Inc.: Employee John D. Diaz-Decaro, PhD, MS, Moderna Therapeutics: Stocks/Bonds
894. One-year mortality and morbidities of severe fever with thrombocytopenia syndrome compared with other diseases: a nationwide cohort study in South Korea
Authors: Heo Namwoo , Heo Seok-Jae , Park Yoon Soo , Yi Seonju , Kim Yong Chan
Published: November 2023

Background

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne disease with high mortality. However, most studies have focused on the short-term mortality of patients with SFTS, and little is known about long-term outcomes in patients with SFTS.

Methods

This retrospective cohort study was conducted using the National Health Insurance Service dataset on hospitalized patients with SFTS aged ≥20 years between 2016 and 2021 (n=1,217). Each SFTS case was matched with three controls hospitalized for non-SFTS-related diseases using propensity score matching. All-cause mortality was evaluated in patients with SFTS during 1-year follow-up and compared with controls. Post-discharge events were investigated to determine the effects of SFTS on post-acute sequelae.

Results

Finally, 1,105 patients with SFTS and 3,315 controls were included. Patients with SFTS had a higher risk of death during the 1-year follow-up than controls (hazard ratio [HR], 2.26; 95% confidence interval [CI], 1.82–2.81). Mortality in the first 30 days was significantly higher in the SFTS group (HR, 3.99; 95% CI, 3.07–5.19) than in the control group. An increased risk of death after 31–365 days was observed in the control group; however, statistical significance was identified only in patients in their 80s (HR, 0.18; 95% CI 0.06–0.57). For the post-discharge events, the SFTS group showed a higher risk of readmission (HR, 1.17; 95% CI, 1.04–1.32) and emergency room visit (HR, 2.32; 95% CI, 1.96–2.76) than the control group.

Conclusion

SFTS is associated with a higher risk of short-term mortality and post-acute sequelae in hospitalized patients during 1-year follow-up than non-SFTS-related diseases. Our results provide evidence for the management of patients with SFTS.

Disclosures

All Authors: No reported disclosures
916. The Transfer of Maternal Antibodies and Dynamics of Maternal and Natural Infection-induced Antibodies against RSV in Children: A Longitudinal Cohort Study
Authors: Wang Qianli , Xu Meng , Wang Yan , Yu Hongjie
Published: November 2023

Background

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infectious disease in children globally. Transplacental-acquired antibodies are essential in protecting infants during the initial months of their life. This study assessed the efficacy of transferring maternal RSV prefusion protein (pre-F) IgG antibodies via the placenta and reported the dynamics of maternal and natural infection-induced antibodies in children.

Methods

A longitudinal mother-neonate pairs cohort was started enrolled in southern China in the autumn of 2013. 660 mother-neonate pairs were included in this study. Both cord blood from neonates and venous blood from mothers at delivery were obtained. The children were followed up and blood samples were collected at ages 2, 4, 6, 12, 24, and 36 months, as well as at 6-8 years (Figure 1). RSV-specific pre-F IgG antibodies were identified by the enzyme-linked immunosorbent assay method. The maternal antibody transfer efficacy, decay of maternal antibodies, age-specific antibody level, and seroprevalence were estimated.

Results

All neonates acquired RSV pre-F IgG antibodies from their mothers. We found a significant correlation between maternal and neonatal antibody titers (ρ=0.86, P< 0.001). The average RSV pre-F IgG antibody titers were higher in cord blood than in maternal blood, with a mean transfer ratio of maternal antibodies of 1.48 (95%CI: 1.44-1.52) (Figure 2). Maternal antibody levels in neonates declined rapidly, with a half-life of 1.4 months. The lowest point of antibodies occurred at 11 months of age, followed by titer increases due to natural RSV infection, and approximately 50% of the children seroconverted at the age of 41.5 months.Figure 2(A) Correlation between neonatal and maternal antibody titer. (B) Transfer ratio with maternal antibody titers. The top orange density plots maternal antibody titers, and the right plots neonatal antibody titers.

Conclusion

Efficient transfer of RSV maternal antibodies to neonates was observed. As maternal antibodies wane, the seropositive infants gradually reduce to the lowest in the first year of life. After that, the infant’s immune system develops and naturally acquired immunity due to infection. Our findings will optimize future strategies for both vaccine and long-term prophylactic monoclonal antibodies to target RSV pre-F protein.

Disclosures

Hongjie Yu, PhD, GlaxoSmithKline: Grant/Research Support|Roche: Grant/Research Support|Sanofi: Grant/Research Support|SINOVAC: Grant/Research Support
929. The different characteristics in renal impairment between severe fever with thrombocytopenia syndrome and hemorrhagic fever with renal syndrome in South Korea
Authors: Ra Sang Hyun , Kwon Hyeonwoo , Kim Geonui , Bae Seongman , Chang Eui Jin , Jung Jiwon , Kim Min Jae , Chong Yong Pil , Lee Sang-Oh , Choi Sang-Ho , Kim Yang Soo , Kim Sung-Han
Published: November 2023

Background

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease with high fatality rate, caused by SFTS virus (officially renamed as Dabie bandavirus). Hemorrhagic fever with renal syndrome (HFRS) is caused by various serotypes under the genus Orthohantavirus and transmitted by aerosolized excreta from rodents. Both have similar clinical manifestations characterized by high-grade fever, thrombocytopenia, hemorrhagic tendencies, and often lead to multiorgan dysfunction including kidneys. However, there are limited data on difference in renal impairment between SFTS and HFRS. We thus investigated the differential characteristics in renal manifestations between SFTS and HFRS in South Korea.

Methods

All adult patients aged ≥ 18 years who were admitted to Asan Medical Center, a 2700-bed tertiary hospital in Seoul, South Korea between August 2005 and September 2022 were retrospectively enrolled. SFTS and HFRS were diagnosed by PCR and serologic confirmation, respectively. Patients with a history of previous urologic or chronic kidney diseases were excluded.

Results

A total of 45 SFTS and 33 HFRS patients were enrolled. Proteinuria and hematuria at admission were observed in 25 (56%) and 19 (42%) for SFTS, and 29 (88%) and 27 (82%) for HFRS, respectively. The 12 (27%) SFTS patients and 26 (78%) HFRS patients initially showed acute kidney injury (AKI). The degree of the hematuria at admission and the presence of AKI were significantly associated with the severity of clinical course in patients with SFTS, not in HFRS (Table 1).Abbreviation. AKI, acute kidney injury; HFRS, hemorrhagic fever with renal syndrome; ICU, intensive care unit; N/A, not assessed; RRT, renal replacement therapy; SFTS, severe fever with thrombocytopenia syndrome. Data represent number of patients (%) unless otherwise specified.

Conclusion

Proteinuria and/or hematuria commonly occurred both in SFTS and HFRS. The presence of hematuria or AKI was associated with worse clinical course in SFTS, but not in HFRS. Thus, in the areas endemic to both diseases, repeated monitoring of kidney function test with urinalysis is required until these two diseases are differentiated.

Disclosures

All Authors: No reported disclosures
1147. A study of high-dose influenza vaccination responses compared to standard-dose in lupus patients: an open- labeled, randomized controlled study
Authors: Yingyounyong Sasicha , Ngamjanyaporn Pintip , Pisitkun Prapaporn , Boonnak Kobporn , Suangtamai Thanitta , Thongpradit Supranee , Rotjanapan Porpon
Published: November 2023

Background

Annual influenza vaccination at standard dosing in the general population is suggested. However, there may be more suitable for lupus patients.

Objectives

To assess the immune responses among lupus patients receiving high dose (HD) and standard (SD) quadrivalent inactivated influenza vaccine, evaluate the adverse events of the HD, and monitor the incidence of influenza infection.

Methods

A randomized parallel design, controlled trial was conducted from March 2021 to May 2022 at Ramathibodi Hospital. All lupus patients were stratified into two groups depending on the depth of immunosuppressive therapy received and randomized to receive either HD or SD in a 1:1 ratio. Patient demographics data and relevant information were retrieved. Blood samples were obtained for hemagglutination inhibition assay (HAI) before vaccination and 4-12 weeks after completion of the vaccination series to determine seroprotection and seroconversion rates.

Results

One hundred twenty-eight lupus patients were enrolled, and 109 individuals completed the HAI analysis. 54/109 patients were in the high- (HI) with mean age (mean ± SD) of 34.3 (25.2-43.4) years, and 55/109 were in the low-immunosuppressive (LI) groups with mean age (mean ± SD) of 38.2 (30.2-46.2) (p=0.018). The majority of patients had a SLEDAI-2K score of 4. The seroprotection rates against H1N1, H3N2/Hongkong, H3N2/Cambodia, B/Victoria, and B/Yamagata strains in HI and LI groups at baseline after the first and second injections were outlined as follows 1.) HI; 74.1%, 82.1%, 76.9%, 75.9%, 79.6%; 85.2%, 89.3%, 88.5%, 85.2%, 88.9%; 89.5%, 89.3%, 88.5%, 93.9%, 88.9%, and 2.) LI; 76.4%, 84.6%, 93.1%, 74.5%, 89.1%; 92.7%, 100%, 100%, 94.5%, 96.4%; 92.7%, 100%, 100%, 94.5%, 94.5%. There was one documented influenza infection during the 9-month follow-up period. The patient was in the LI group and received the SD vaccine. 19/109 (17.4%) patients had grade 1 adverse events with no difference between SD and HD.

Conclusion

Lupus patients’ immune response, especially those taking HI, may not be similar to healthy individuals. A higher dosage of influenza vaccination may provide a better seroprotection rate. However, real-world clinical effectiveness is yet to demonstrate, and further studies are required.

Disclosures

All Authors: No reported disclosures
1155. Coadministration of Intranasal M2SR (M2-deficient Single Replication) Investigational Influenza Vaccine with Fluzone High Dose Induces Superior Immune Responses to Fluzone High Dose Alone in 65-85 Year Old Adults
Authors: Eiden Joseph , Fierro Carlos , White Alexander , Davis Matthew , Rhee Margaret , Turner Mark , Murray Bryan , Herber Renee , Aitchison Roger , Marshall David , Moser Michael , Bilsel Pamuk
Published: November 2023

Background

Adults over age 65 years exhibit increased susceptibility to influenza viruses, accounting for 70-85% of annual influenza-related US fatalities. Licensed vaccines mainly induce serum humoral immunity and remain the primary method of influenza prevention, but vaccine effectiveness (VE) remains particularly low in older individuals (Fig 1). Stimulation of mucosal antibodies and T cells, immune effectors also associated with protection against influenza, are anticipated to enhance VE.

Methods

A randomized, double-blind, double-dummy, placebo-controlled Phase 1b study (NCT05163847) was conducted at 6 US study sites with the investigational intranasal M2SR (M2 deficient Single Replication) and Fluzone High Dose (HD) vaccine that contained HA & NA from A/Cambodia/e0826360/2020 (Cam2020). Adults aged 65-85 years (n = 305) received either one administration of Cam2020 M2SR alone, Cam2020 M2SR along with HD, HD alone, or placebo (Table 1). Demographics were comparable across cohorts (Table 2).

Results

Study vaccination was well-tolerated. Intranasal M2SR generated significantly increased serum HAI and NAI antibodies compared with placebo (Fig 2). Moreover, M2SR coadministered with HD induced HAI and NAI antibodies in significantly higher proportion of subjects than HD alone (Fig 2). M2SR alone and M2SR coadministered with HD elicited significant mucosal secretory IgA (sIgA) antibodies against vaccine antigen, Cam2020, and drifted H3N2 Darwin2021 strain (Fig 3). Similarly, T cells positive for IFNg and GrzB secretion were significantly induced by M2SR only or by M2SR coadministered with HD (Fig 4). HD alone did not induce mucosal antibodies or T cell responses (Figs 3 & 4).

Conclusion

Coadministration of intranasal M2SR with intramuscular Fluzone HD resulted in a multi-faceted immune response in older adults aged 65-85 years old with a higher proportion of responders across all immune measurements compared with either vaccine alone. Coadministration of the two vaccines resulted in significant rises in serum HAI and NAI titers compared to HD alone (Fig 5). These broad immune responses support the potential for the safe coadministration of M2SR with HD to enhance protection against influenza infection in this highly vulnerable age group.

Disclosures

Joseph Eiden, MD, PhD, FluGen, Inc.: Advisor/Consultant Bryan Murray, M.D., FluGen, Inc.: Advisor/Consultant Renee Herber, B.S., FluGen, Inc.: Salary Roger Aitchison, ScM, FluGen, Inc.: Advisor/Consultant David Marshall, B.S., FluGen, Inc.: salary Michael Moser, Ph.D., FluGen, Inc.: salary Pamuk Bilsel, Ph.D., FluGen, Inc.: salary
Greening the G7 economies
Authors: Barbier Edward B
Published: November 2023

Despite some progress, the Group of 7 (G7) have yet to act collectively to foster a low-carbon transition of their economies. This paper outlines such a strategy, which would also encourage other economies to follow suit. This strategy has three elements: fossil fuel pricing reforms; recycling revenues to fund green innovation and to offset any adverse income or employment impacts; and developing the proposed G7 Climate Club to promote compliance by other countries. This must be accompanied by comprehensive assistance to emerging market and developing economies to help accelerate their clean energy transition, facilitate their participation in the Climate Club, and attain climate, poverty and development goals.
Inter-Organellar Effects of Defective ER-Localized Linolenic Acid Formation on Thylakoid Lipid Composition, Non-Photochemical Quenching of Chlorophyll Fluorescence and Xanthophyll Cycle Activity in the Arabidopsis fad3 Mutant
Authors: Matzner Monique , Launhardt Larissa , Barth Olaf , Humbeck Klaus , Goss Reimund , Heilmann Ingo
Published: November 2023

Monogalactosyldiacylglycerol (MGDG) is the main lipid constituent of thylakoids and a structural component of photosystems and photosynthesis-related proteo-lipid complexes in green tissues. Previously reported changes in MGDG abundance upon stress treatments are hypothesized to reflect mobilization of MGDG-based polyunsaturated lipid intermediates to maintain extraplastidial membrane integrity. While exchange of lipid intermediates between compartmental membranes is well documented, physiological consequences of mobilizing an essential thylakoid lipid, such as MGDG, for an alternative purpose are not well understood. Arabidopsis seedlings exposed to mild (50 mM) salt treatment displayed significantly increased abundance of both MGDG and the extraplastidial lipid, phosphatidylcholine (PC). Interestingly, similar increases in MGDG and PC were observed in Arabidopsis fad3 mutant seedlings defective in endoplasmic reticulum (ER)–localized linolenic acid formation, in which compensatory plastid-to-ER-directed mobilization of linolenic acid–containing intermediates takes place. The postulated (salt) or evident (fad3) plastid–ER exchange of intermediates concurred with altered thylakoid function according to parameters of photosynthetic performance. While salt treatment of wild-type seedlings inhibited photosynthetic parameters in a dose-dependent manner, interestingly, untreated fad3 mutants did not show overall reduced photosynthetic quantum yield. By contrast, we observed a reduction specifically of non-photochemical quenching (NPQ) under high light, representing only part of observed salt effects. The decreased NPQ in the fad3 mutant was accompanied by reduced activity of the xanthophyll cycle, leading to a reduced concentration of the NPQ-effective pigment zeaxanthin. The findings suggest that altered ER-located fatty acid unsaturation and ensuing inter-organellar compensation impacts on the function of specific thylakoid enzymes, rather than globally affecting thylakoid function.
Reply to Juliana Gómez-Quintero, Spencer Chainey, and Hervé Borrion, ‘A Method for Organized Crime Harm Assessment: Connecting Associated Crimes’
Authors: Greenfield Victoria A , Paoli Letizia
Published: November 2023

In this article we reply to the article “A Method for Organized Crime Harm Assessment: Connecting Associated Crimes”, which Juliana Gómez-Quintero, Spencer Chainey, and Hervé Borrion published in Policing. Our criticisms are twofold: (1) it mischaracterizes our method, the “Harm Assessment Framework,” which we first presented in 2013 in complementary articles and, consequently, it delivers unwarranted criticisms of our framework; (2) it, relatedly, does not fully recognize the many ways in which the authors’ proposed ‘Organized Crime Harm Assessment’ (OCHA) draws from our framework and, by extension, it overstates the OCHA’s novelty. In addition, we react to a further, more plausible criticism of our method and discuss some apparent weaknesses of the proposed OCHA. Finally, we re-emphasize our conviction that assessing the consequences of criminal policies—especially on organized crime—is a crucial undertaking that has the potential to improve the effectiveness, justification, and legitimacy of the policies.
Characterization of digital annular pulleys and their entheses: an ultrasonographic study with anatomical and histological correlations
Authors: Coronel Luis , Mandl Peter , Miguel-Pérez Maribel , Blasi Joan , D’Agostino Maria Antonietta , Martinoli Carlo , Bong David A , Möller Ingrid
Published: November 2023

Objectives

Digital annular pulleys (DAPs) are important anatomical structures for finger function. The anatomy, histology and imaging assessment of DAPs, particularly at the level of their entheses, are still not clearly defined. The advent of high-frequency US transducers opened new perspectives in evaluating submillimetre-scale structures, such as pulleys, paving the way for their global assessment. The study aimed to characterize DAPs from an anatomical, histological and US perspective, focusing on the detection and complete description of pulley entheses.

Methods

US assessment and gross anatomy dissection were conducted on 20 cadaveric hands to study DAP thickness and structure, including enthesis identification. The results of the US and anatomical measurements were correlated. DAP entheses identified by US were characterized via histological analysis. DAPs in 20 healthy controls (HCs) were detected and measured by US. The A1, A2 and A4 DAP entheses were assessed using a new dynamic manoeuvre to better evaluate those structures.

Results

A total of 1200 DAPs (400 cadaveric, 800 HCs) were analysed. The cadaveric study demonstrated strong correlation between anatomical and US measurement of DAPs (r = 0.96). At the histological level, DAP entheses at the volar plate, sesamoid bones or phalangeal ridges contained fibrous and fibrocartilaginous tissue. US assessment of A1, A2 and A4 DAPs in HCs allowed the identification of 718/720 (99.73%) entheses.

Conclusion

US is an effective tool to detect and study DAPs. DAP entheses reveal both fibrous and fibrocartilaginous characteristics. A newly described manoeuvre to optimize DAP enthesis visualization enhances their detection by US.
Having Social Media among Integrated Plastic Surgery Applicants: Is It Needed to Match?
Authors: Yang Alan Z. , Bustos Valeria P. , Manstein Samuel M. , Comer Carly D. , Foster Lacey , Sarac Benjamin A. , Janis Jeffrey E. , Lin Samuel J.
Published: November 2023

Background:

Little information exists on the perceptions of integrated plastic and reconstructive surgery (PRS) residency applicants on the need for having social media (SoMe) during the application process.

Methods:

A cross-sectional survey study was conducted during the 2022 match cycle to assess integrated PRS residency applicants’ perceptions on the role of SoMe during the match. Univariate and multivariate analyses were performed on variables of interest. Qualitative analysis was conducted on free-form responses.

Results:

Seventy-nine surveys were completed (response rate: 24%). The majority of respondents were educated in the United States (92%). Instagram was the most commonly used SoMe platform (92%). Of those surveyed, 18% thought that SoMe was beneficial to the application process. Twenty-nine percent of respondents agreed that a SoMe presence increases one’s chances of matching into PRS residency (41% disagreed and 30% responded neutrally). Forty-four percent endorsed stress about maintaining a SoMe presence in PRS. Having mentors who recommended maintaining a SoMe presence was associated with the belief that SoMe increases one’s chances of matching [odds ratio (OR) 8.1, 95% confidence interval (CI) 1.1–40.4, P = 0.011] and stress about maintaining a SoMe presence (OR 6.3, 95% CI 1.2–33.3, P = 0.030). Applicants who did research years had lower odds of experiencing stress (OR 0.16, 95% CI 0.04–0.70, P = 0.015).

Conclusions:

The growing role of SoMe in the residency selection process may be exacerbating applicants’ stress and anxiety. PRS programs may consider establishing clear policies for how SoMe will be used in evaluating candidates.
Osteocutaneous Radial Forearm Flap: Harvest Technique and Prophylactic Volar Locked Plating
Authors: Capito Anthony E. , Hansen Brian K. , Schmitt Mark W. , Beck Jadon H. , Cripe Brian A. , Apel Peter J.
Published: November 2023

Background:

The osteocutaneous radial forearm (OCRF) flap is a variation of the traditional radial forearm flap with incorporation of an anterolateral segment of corticocancellous bone of the radius, periosteum, and overlying skin. The OCRF flap is indicated in traumatic injuries or extirpation defects with segmental bone loss and is well suited to foot and ankle reconstruction due to its thin pliable skin.

Methods:

In this single-center case series, a retrospective review was conducted to identify patients who underwent OCRF free flap for foot and ankle reconstruction that required harvest of more than 50% of the cross-sectional area of the radius with prophylactic volar locked plating of the donor site. Outcome measures included flap failure rates, postoperative fracture, thrombotic events, time to follow-up, and time to full weightbearing. Flap harvest technique is extensively discussed.

Results:

Six cases were included in this series. There were no flap failures or thrombotic events. Recipient site healing was confirmed in all patients, with partial distal skin paddle loss in one patient requiring operative debridement. No patients sustained donor site complications or functional impairment. Full lower extremity weightbearing was achieved at 12.4 ± 3.3 weeks after surgery.

Conclusions:

The OCRF free flap transfer provides a reliable means of obtaining thin, supple soft tissue coverage with a large, vascularized segment of bone for reconstruction in the foot and ankle. Here, we describe use of more than 50% of the cross-sectional area of the radius with volar locked prophylactic plating. These updates expand use of this reconstructive technique.
Trauma Patient Transitions From Critical Care: A Survey of U.S. Trauma Centers
Authors: Saucier Jason A. , Dietrich Mary S. , Maxwell Cathy , Lane-Fall Meghan Brooks , Minnick Ann
Published: November 2023

BACKGROUND:

Transitions between clinical units are vulnerable periods for patients. A significant body of evidence describes the importance of structured transitions, but there is limited reporting of what happens. Describing transitions within a conceptual model will characterize the salient forces that interact during a patient transition and, perhaps, lead to improved outcomes.

OBJECTIVE:

To describe the processes and resources that trauma centers use to transition patients from critical care to nonintensive care units.

METHODS:

This cross-sectional study surveyed all Level I and II trauma centers listed in the American Trauma Society database from September 2020 to November 2020. Data were merged from the American Hospital Association 2018 Hospital Survey.

RESULTS:

A total of 567 surveys were distributed, of which 152 responded for a (27%) response rate. Results were organized in categories: capital input, organizational facets, employee behavior, employee terms/scope, and labor inputs. Resources and processes varied; the most important opportunities for transition improvement included: (1) handoff instruments were only reported at 36% (n = 27) of trauma centers, (2) mandatory resident education about transitions was only reported at 70% (n = 16) of trauma centers, and (3) only 6% (n = 4) of trauma centers reported electronic medical record applications that enact features to influence employee behavior.

CONCLUSIONS:

After years of focusing on transitions as a high-stake period, there remain many opportunities to develop resources and enact effective processes to address the variability in transition practice across trauma centers.
Right ventricular infarction: epidemiological, clinical, and angiographic characteristics and the outcomes through the experience of a Moroccan cardiology department
Authors: Bouhaddoune Youssra , Bouchlarhem Amine , Bazid Zakaria , Ismaili Nabila , El Ouafi Noha
Published: November 2023

Background:

Acute myocardial infarction (MI) is a major cause of cardiovascular mortality, which is the leading cause of death in the world. Our objective in this study was to evaluate the epidemiological, clinical, and angiographic features of right ventricular infarction (RVI), as well as its complications and its therapeutic approaches.

Patients and methods:

It is a single-centered retrospective descriptive study conducted over a period of 2 years from November 2018 to October 2020. The authors included 82 patients with RVI hospitalized in the cardiovascular ICU during the initial phase of acute coronary syndrome with persistent ST segment elevation. Patients who were diagnosed with RVI at electrocardiogram and echocardiography were recruited.

Results:

The authors included 500 patients hospitalized for STEMI, 82 had MI extended to the RV, reflecting a rate of 16.4%. The mean age in our study was 64±12.3 years. Dyslipidemia, diabetes mellitus, and hypertension were the most common cardiovascular risk factors among these patients. RVI co-existed with inferior MI in 62.2 of cases and in 37.8% of anterior MI, while isolated RVI was seen in only one patient. Transthoracic echocardiography showed right ventricular (RV) systolic dysfunction in 24.39% of cases, while RV dilatation was seen in only 10.9% of patients. Therapeutic approach was based essentially on revascularization with thrombolysis and coronary angiography +/- PCI. The percentage of mortality was 2.4%.

Conclusion:

RVI is relatively rare and is mostly related to an extension of an inferior MI. Early diagnosis, prompt treatment, and appropriate are the keys to improve prognosis, and reduce complications.
Characterization of Haloarcula terrestris sp. nov. and reclassification of a Haloarcula species based on a taxogenomic approach
Authors: Straková Dáša , Galisteo Cristina , de la Haba Rafael R. , Ventosa Antonio
Published: November 2023

An extremely halophilic archaeon, strain S1AR25-5AT, was isolated from a hypersaline soil sampled in Odiel Saltmarshes Natural Area (Huelva, Spain). The cells were Gram-stain-negative, motile, pleomorphic rods. Cell growth was observed in the presence of 15–30 % (w/v) NaCl [optimum, 25 % (w/v) NaCl], at pH 6.0–9.0 (optimum, pH 6.5–7.5) and at 25–50 °C (optimum, 37 °C). Based on the 16S rRNA and rpoB′ gene sequence comparisons, strain S1AR25-5AT was affiliated to the genus

Haloarcula

. Taxogenomic analysis, including comparison of the genomes and the phylogenomic tree based on the core-orthologous proteins, together with the genomic indices, i.e., orthologous average nucleotide identity, digital DNA–DNA hybridization and average amino acid identity, confirmed that strain S1AR25-5AT (=CCM 9249T=CECT 30619T) represents a new species of the genus

Haloarcula

, for which we propose the name Haloarcula terrestris sp. nov. The major polar lipids were phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester, phosphatidylglycerol sulphate and an unidentified glycolipid, which correlated with the lipid profile of species of the genus

Haloarcula

. In addition, based on the modern approach in description of species in taxonomy of prokaryotes, the above mentioned genomic indexes indicated that the species

Haloarcula tradensis

should be considered as a heterotypic synonym of

Haloarcula argentinensis

.
Establishment of pseudorabies virus latency and reactivation model in mice dorsal root ganglia culture
Authors: Li Lin-Tao , Liu Jie , Luo Miao , Liu Jing-Song , Zhang Mei-Mei , Zhang Wen-Jing , Chen Huan-Chun , Liu Zheng-Fei
Published: November 2023

Pseudorabies virus (PRV) belongs to the alpha herpesvirus family and is responsible for Aujeszky’s disease in pigs. Similar to other alpha herpesviruses, PRV establishes a lifelong latent infection in trigeminal ganglion. These latently infected pigs serve as a reservoir for recurrent infections when reactivation is triggered, making the eradication of PRV a challenging task. However, the molecular mechanism underlying PRV latency and reactivation in neurons is still poorly understood due to limitations in the in vitro model. To establish a pseudorabies virus latency and reactivation model in primary neuron cultures, we isolated dorsal root ganglion (DRG) from newborn Kunming mice using a method named epineurium-pulling for DRG collection (EPDC) and cultured primary neurons in vitro. A dual-colour recombinant PRV BAC mRuby-VP16 was constructed and 0.5 multiplicity of infection (MOI) was found as an appropriate dose in the presence of aciclovir to establish latency. Reactivation was induced using UV-inactivated herpesviruses or a series of chemical inhibitors. Interestingly, we found that not only UV-PRV, but also UV-HSV-1 and UV-BHoV-5 were able to induce rapid PRV reactivation. The efficiency of reactivation for LY294002, forskolin, etoposide, dexamethasone, and acetylcholine was found to be dependent on their concentration. In conclusion, we developed a valuable model of PRV latency and reactivation, which provides a basis for future mechanism research.
Streptomyces: a natural source of anti-Candida agents
Authors: Martins Nathália da Rosa Coelho , Rodrigues da Silva Aldo , Ratcliffe Norman , Evangelho Victor Gustavo Oliveira , Castro Helena Carla , Quinn Gerry A.
Published: November 2023

Introduction. There is an urgent need to source new compounds that can combat the current threat of serious infection caused by Candida spp. and contend with the problem of antimicrobial resistance.

Gap. A synthesis of the evidence available from the current literature is needed to identify promising antifungal chemotherapeutics.

Aim. To highlight anti-Candida compounds derived from

Streptomyces

spp. (a well-known source of antimicrobial compounds) that could translate to potential candidates for future clinical practice.

Methodology. A comprehensive review was conducted across three scientific literature databases spanning a 13-year period.

Results. We identified 151 compounds with anti-Candida activity. Amongst these, 40 were reported with very strong inhibitory activity, having minimum inhibitory concentrations (MICs) against Candida spp. of <3.5 µg ml−1, 66 compounds were considered strong inhibitors and 45 compounds exhibited moderate inhibitory potential. From an analysis of the MICs, we deduced that the actinomycin-like compounds RSP01 and RSP02 were probably the most promising anti-Candida compounds. Other antifungals of note included filipin-like compounds, which demonstrated superior inhibition to amphotericin B and activity against Candida glabrata and Candida krusei, and bafilomycin derivatives, which had substantial inhibition against Candida parapsilosis.

Conclusion. It is essential to recognize the limitations inherent in the quest for new antifungals, which encompass toxicity, in vivo effectiveness and constraints associated with limited data access. However, further investigation through in-depth study and emerging technologies is of paramount importance, given that there are still many more compounds to discover. This review highlights the importance of antifungal compounds derived from

Streptomyces

, which demonstrate robust inhibition, and, in many cases, low toxicity, making them promising candidates for the development of novel antifungal agents.
Assessing the Effectiveness of ChatGPT as a Clinical Trainee: A Study on the Diagnostic Value of Large Language Models in a Complex Clinical Environment
Authors: Craig David , Nugent Chris
Published: November 2023

We tested the performance of Chat Generative Pre-trained Transformer (ChatGPT) in the role of a trainee clinician (Specialist Registrar or Resident) undergoing direct assessment by a human supervising specialist clinician (Consultant or Attending). The session consisted of a hospital ward round scenario presented to three versions of ChatGPT, namely OpenAI ChatGPT-3.5, Bing ChatGPT-4 and OpenAI ChatGPT-4. A specific test of memory and context was included via an end-of-teaching educator feedback exercise. Only OpenAI ChatGPT-4 provided responses comparable to the standard a trainee might offer during progress towards completion of training and specialist accreditation. Bing ChatGPT-4 responded with several clinically dubious statements, often in a repetitive and detached way, and was unable to retain awareness of the purpose of the session and the identities of participants.
Leveraging a large language model to predict protein phase transition: a physical, multiscale and interpretable approach
Authors: Frank Mor , Ni Pengyu , Jensen Matthew , Gerstein Mark B
Published: November 2023

Protein phase transitions (PPTs) from the soluble state to a dense liquid phase (forming droplets via liquid-liquid phase separation) or to solid aggregates (such as amyloids) play key roles in pathological processes associated with age-related diseases such as Alzheimer’s disease. Several computational frameworks are capable of separately predicting the formation of droplets or amyloid aggregates based on protein sequences, yet none have tackled the prediction of both within a unified framework. Recently, large language models (LLMs) have exhibited great success in protein structure prediction; however, they have not yet been used for PPTs. Here, we fine-tune a LLM for predicting PPTs and demonstrate its usage in evaluating how sequence variants affect PPTs, an operation useful for protein design. In addition, we show its superior performance compared to suitable classical benchmarks. Due to the ”black-box” nature of the LLM, we also employ a classical random forest model along with biophysical features to facilitate interpretation. Finally, focusing on Alzheimer’s disease-related proteins, we demonstrate that greater aggregation is associated with reduced gene expression in AD, suggesting a natural defense mechanism.

Significance Statement

Protein phase transition (PPT) is a physical mechanism associated with both physiological processes and age-related diseases. We present a modeling approach for predicting the protein propensity to undergo PPT, forming droplets or amyloids, directly from its sequence. We utilize a large language model (LLM) and demonstrate how variants within the protein sequence affect PPT. Because the LLM is naturally domain-agnostic, to enhance interpretability, we compare it with a classical knowledge-based model. Furthermore, our findings suggest the possible regulation of PPT by gene expression and transcription factors, hinting at potential targets for drug development. Our approach demonstrates the usefulness of fine-tuning a LLM for downstream tasks where only small datasets are available.
DNA Methylation (DM) data format and DMtools for efficient DNA methylation data storage and analysis
Authors: Zhou Qiangwei , Zhou Cong , Zhu Zhixian , Sun Yuanhui , Li Guoliang
Published: November 2023

DNA methylation is a critical epigenetic mechanism that plays a pivotal role in various biological processes. Currently, larger datasets from whole-genome bisulfite sequencing for DNA methylation pose challenges throughout the computational analysis pipeline, including storage and memory constraints. Unfortunately, storage formats and analysis tools have not kept pace with these increased resource demands. In this study, we present a new and efficient design for storing DNA methylation (DM) data after mapping in compressed binary indexed DM format. Our format significantly reduces storage space by 80%-95% compared to commonly used file formats for DNA methylation data after mapping. To enhance the processing of DNA methylation data in DM format, we have developed DMtools, a comprehensive toolkit that offers utilities such as rapid and random access, computation of DNA methylation profiles across genes, and analysis of differential DNA methylation. The analysis speed is improved by over 100 times compared to existing methods. Furthermore, we have created pyDMtools, a Python package that efficiently processes DM format files for Python users. The integration of the DM format and its associated tools represents significant progress in handling and exploring DNA methylation data, offering the potential to significantly reduce storage needs and improve downstream analysis capabilities.