bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep enteroscopy – what's new and what works best?
Authors: Tuck Jaclyn , Lizaola-Mayo Blanca C. , Leighton Jonathan A.
Published: April 2024

Purpose of review

We aim to review the types of device-assisted deep enteroscopy endoscopes, tips for a successful procedure as well as areas for improvement.

Recent findings

Deep enteroscopy allows for diagnostic and therapeutic intervention of the small bowel and can be used as an adjunct to video capsule endoscopy to improve the yield and management of small bowel lesions.

Our top tips for deep enteroscopy success include reviewing patient history and prior imaging, utilizing CO2 insufflation or water exchange, verifying quality measures and emphasizing ergonomics. With these, endoscopists can optimize patient outcomes while minimizing occupational risks. New aspects of deep enteroscopy equipment focus on high-resolution imaging, a larger working channel, and enhanced scope angulation. Proposed improvements include developing innovative technology to optimize the color and clarity of the high-resolution imaging, minimizing the number of staff required for the procedure, and decreasing ergonomic strain.
Insights Into Treatment Alternatives for Neurosyphilis: Systematic Literature Review and Meta-Analysis
Authors: Callado Gustavo Yano , Pardo Isabele , Gutfreund Maria Celidonio , Deliberato Rodrigo Octávio , Holubar Marisa , Salinas Jorge L. , Marra Christina M. , Perencevich Eli N. , Marra Alexandre R.
Published: April 2024

We conducted a systematic literature review and meta-analysis to assess the efficacy of alternative treatments for neurosyphilis. We searched MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Embase, Cochrane, Scopus, and Web of Science from database inception to September 2023, for studies in neurosyphilis that compared penicillin monotherapy with other treatments. We focused on the impact of these therapies on treatment response, but also assessed data regarding reinfection and adverse drug events. Random-effect models were used to obtain pooled mean differences. Of 3415 screened studies, 6 met the inclusion criteria for the systematic literature review. Three studies provided quantitative data that allowed for inclusion in the meta-analysis. Our analysis revealed that the efficacy of intravenous (IV) ceftriaxone 2 g daily for 10 days (51 patients) did not appear statistically different compared with IV penicillin G 18 to 24 million units daily for 10 days (185 patients) for neurosyphilis (pooled odds ratio, 2.85; 95% confidence interval, 0.41–19.56; I2 = 49%). No statistical difference between ceftriaxone and penicillin was identified in people living with human immunodeficiency virus (HIV) (pooled odds ratio, 4.51; 95% confidence interval, 0.50–40.49; I2 = 34%). We concluded that alternative therapy with IV ceftriaxone appears similar to penicillin, potentially expanding treatment options for neurosyphilis. Other treatment options including doxycycline warrant further study.
Erythrasma of the Vulva: An Invisible Dermatosis
Authors: Jobbagy Soma , Laga Alvaro C. , Watkins Jaclyn C.
Published: April 2024

Erythrasma is a prevalent superficial bacterial infection typically caused by Corynebacteria species and preferentially affecting intertriginous sites including axillary, interdigital, and inguinal skin folds. However, erythrasma of the vulva is uncommon, with only 2 cases previously reported. Although erythrasma can be diagnosed clinically using Woods lamp examination, it may not always be considered in the differential diagnosis for patients presenting with persistent vulvar pruritus. We report 12 cases of vulvar erythrasma identified by histopathology, with a review of clinical and histologic features. The mean patient age was 60.1 yr and the mean patient BMI was 30.5. Five of 12 patients presented with pruritic rash. The time from symptom onset to diagnosis was 9 mo in 1 case, >18 mo in 4 cases, and unknown in the remaining cases. The characteristic histologic features were compact orthokeratosis and mild perivascular chronic inflammation. In all 12 cases, Periodic Acid-Schiff-diastase (PAS-D) staining highlighted intracorneal filamentous rods which were not readily appreciable on H&E. After the diagnosis of erythrasma, 4 patients were treated with topical lincomycin, of whom 3 had clinical improvement in symptoms. One patient was treated with topical macrolide antibiotic and also reported improvement in symptoms. Consideration of erythrasma on the differential for patients presenting with vulvar rash and pruritus may shorten the time to diagnosis and treatment, minimize patient discomfort, and reduce the scope and cost of diagnostic testing.
Early fluid plus norepinephrine resuscitation diminishes kidney hypoperfusion and inflammation in septic newborn pigs
Authors: Fanous Mina S. , de la Cruz Julia E. , Michael Olugbenga S. , Afolabi Jeremiah M. , Kumar Ravi , Adebiyi Adebowale
Published: April 2024

Sepsis is the most frequent risk factor for acute kidney injury (AKI) in critically ill infants. Sepsis-induced dysregulation of kidney microcirculation in newborns is unresolved. The objective of this study was to use the translational swine model to evaluate changes in kidney function during the early phase of sepsis in newborns and the impact of fluid plus norepinephrine (NE) resuscitation. Newborn pigs (3-7-day-old) were allocated randomly to three groups: 1) Sham, 2) Sepsis (cecal ligation and puncture; CLP) without subsequent resuscitation, and 3) Sepsis with Lactated Ringer plus NE resuscitation. All animals underwent standard anesthesia and mechanical ventilation. Cardiac output (COP) and glomerular filtration rate (GFR) were measured non-invasively. Mean arterial pressure (MAP), total renal blood flow (RBF), cortical perfusion (coPf), medullary perfusion (mePf), and medullary tissue oxygen tension (mtPO2) were determined for 12 h. CLP decreased MAP and COP by more than 50%, with a proportional increase in renal vascular resistance (RVR) and a 60-80% reduction in RBF, coPf, mePf, and mtPO2compared to sham. CLP also decreased GFR by ~79% and increased AKI biomarkers. Isolated foci of tubular necrosis were observed in the septic piglets. Except for mtPO2, changes in all these parameters were ameliorated in resuscitated piglets. Resuscitation also attenuated sepsis-induced increases in the levels of plasma C-reactive protein, proinflammatory cytokines, lactate dehydrogenase, alanine transaminase, aspartate aminotransferase, and renal NLRP3 inflammasome. These data suggest that newborn pigs subjected to CLP develop hypodynamic septic AKI. Early implementation of resuscitation lessens the degree of inflammation, AKI, and liver injury.
Interplay between brain oxygenation and the development of hypothermia in endotoxic shock
Authors: Moretti Eduardo H. , Lino Caroline A. , Steiner Alexandre A.
Published: April 2024

There is evidence to suggest that the hypothermia observed in the most severe cases of systemic inflammation or sepsis is a regulated response with potential adaptive value, but the mechanisms involved are poorly understood. Here, we investigated the interplay between brain oxygenation (assessed by tissue PO2) and the development of hypothermia in unanesthetized rats challenged with a hypotension-inducing dose of bacterial lipopolysaccharide (LPS, 1 mg/kg i.v.). At an ambient temperature of 22 °C, oxygen consumption (V̇O2) began to fall only a few minutes after the LPS injection, and this suppression in metabolic rate preceded the decrease in core temperature. No reduction in brain PO2 was observed prior to the development of the hypometabolic, hypothermic response, ruling out the possibility that brain hypoxia served as a trigger for hypothermia in this model. Brain PO2 was even increased. Such an improvement in brain oxygenation could reflect either an increased O2 delivery or a decreased O2 consumption. The former explanation seems unlikely because blood flow (cardiac output) was being progressively decreased during the recording period. On the other hand, the decrease in V̇O2 usually preceded the rise in PO2, and an inverse correlation between V̇O2 and brain PO2 was consistently observed. These findings do not support the existence of a closed-loop feedback relationship between brain oxygenation and hypothermia in systemic inflammation. The data are consistent with a feedforward mechanism in which hypothermia is triggered (possibly by cryogenic inflammatory mediators) in anticipation of changes in brain oxygenation to prevent the development of tissue hypoxia.
Herpes simplex virus-1 susceptibility as a risk factor for sepsis, with cytomegalovirus susceptibility elevating severity: insights from a bidirectional Mendelian randomization study
Authors: Shi Wenjun , Lin Qiao , Zhang Meng , Ouyang Nengtai , Zhang Yin , Yang Zhengfei
Published: April 2024

Objective

We conducted a two-sample bidirectional Mendelian randomization (MR) study to investigate the causal relationships between herpes viruses and sepsis.

Methods

Publicly available genome-wide association study (GWAS) data were used. Four viruses, HSV-1, HSV-2, EBV and CMV, were selected, with serum positivity and levels of antibody in serum as the herpes virus data.

Results

In forward MR, susceptibility to HSV-1 was a risk factor for sepsis. The susceptibility to CMV showed a severity-dependent effect on sepsis and was a risk factor for the 28-day mortality from sepsis, and was also a risk factor for 28-day sepsis mortality in critical care admission. EBV EA-D antibody level after EBV infection was a protective factor for 28-day sepsis mortality in critical care admission, and CMV pp28 antibody level was a risk factor for 28-day sepsis mortality in critical care admission. No statistically significant causal relationships between HSV-2 and sepsis were found. No exposures having statistically significant association with sepsis critical care admission as an outcome were found. In reverse MR, the sepsis critical care admission group manifested a decrease in CMV pp52 antibody levels. No causal relationships with statistical significance between sepsis exposure and other herpes virus outcomes were found.

Conclusions

Our study identifies HSV-1 susceptibility as a sepsis risk, with CMV susceptibility elevating severity. Varied effects of EBV and CMV antibodies on sepsis severity are noted. Severe sepsis results in a decline in CMV antibody levels. Our results help prognostic and predictive enrichment and offer valuable information for precision sepsis treatment.
Endogenous β3-adrenergic receptor activation alleviates sepsis-induced cardiomyocyte apoptosis via PI3K/Akt signaling pathway
Authors: Xing Yun , Tian Tian , Zhang Xue , Yang Duomeng , Zhang Chanjuan , Wang Miao , Wang Yiyang , Luo Tao , Wang Zhi , Wang Huadong , Li Hongmei
Published: April 2024

β3-adrenergic receptor (β3-AR) has been proposed as a new therapy for several myocardial diseases. However, the effect of β3-AR activation on sepsis-induced myocardial apoptosis is unclear. Here, we investigated the effect of β3-AR activation on the cardiomyocyte apoptosis and cardiac dysfunction in cecal ligation and puncture (CLP)-operated rats and lipopolysaccharide (LPS)-treated cardiomyocytes. We found that β3-AR existed both in adult rat ventricular myocytes (ARVMs) and H9c2 cells. The expression of β3-AR was upregulated in LPS-treated ARVMs and the heart of CLP rats. Pretreatment with β3-AR agonist, BRL37344, inhibited LPS-induced cardiomyocyte apoptosis and caspase-3, -8 and -9 activation in ARVMs. BRL37344 also reduced apoptosis and increased the protein levels of PI3K, p-AktSer473 and p-eNOSSer1177 in LPS-treated H9c2 cells. Inhibition of PI3K using LY294002 abolished the inhibitory effect of BRL37344 on LPS-induced caspase-3, -8, and -9 activation in H9c2 cells. Furthermore, administration of β3-AR antagonist, SR59230A (5 mg/kg), significantly decreased the maximum rate of left ventricular pressure rise (+dP/dt) in CLP-induced septic rats. SR59230A not only increased myocardial apoptosis, reduced p-AktSer473 and Bcl-2 contents, but also increased mitochondrial Bax, cytoplasm cytochrome c, cleaved caspase-9 and cleaved caspase-3 levels of the myocardium in septic rats. These results suggest that endogenous β3-AR activation alleviates sepsis-induced cardiomyocyte apoptosis via PI3K/Akt signaling pathway and maintains intrinsic myocardial systolic function in sepsis.
OMX: A NOVEL OXYGEN DELIVERY BIOTHERAPEUTIC IMPROVES OUTCOMES IN AN OVINE MODEL OF CONTROLLED HEMORRHAGIC SHOCK
Authors: Maltepe Emin , Smith Michael , Boehme Jason , Datar Sanjeev A. , Hutchings Rachel S. , Vento Christian A. , Manzoor Hadiya , Loucks Alexandra , Winger Jonathan A. , Fineman Jeffrey R.
Published: April 2024

Hemorrhagic shock is a major source of morbidity and mortality worldwide. While whole blood or blood product transfusion is a first-line treatment, maintaining robust supplies presents significant logistical challenges, particularly in austere environments. OMX is a novel nonhemoglobin (Hb)-based oxygen carrier derived from the H-NOX (heme-nitric oxide/oxygen binding) protein family. Because of their engineered oxygen (O2) affinities, OMX proteins only deliver O2 to severely hypoxic tissues. Additionally, unlike Hb-based oxygen carriers, OMX proteins do not scavenge nitric oxide in the vasculature. To determine the safety and efficacy of OMX in supporting tissue oxygen delivery and cardiovascular function in a large animal model of controlled hemorrhage, 2–3-week-old lambs were anesthetized, intubated, and mechanically ventilated. Hypovolemic shock was induced by acute hemorrhage to obtain a 50% reduction over 30 min. Vehicle (n = 16) or 400 mg/kg OMX (n = 13) treatment was administered over 15 min. Hemodynamics, arterial blood gases, and laboratory values were monitored throughout the 6-h study. Comparisons between groups were made using t tests, Wilcoxon rank sum test, and Fisher’s exact test. Survival was assessed using Kaplan-Meier curves and the log-rank test. We found that OMX was well-tolerated and significantly improved lactate and base deficit trends, and hemodynamic indices (P < 0.05). Median survival time was greater in the OMX-treated group (4.7 vs. 6.0 h, P < 0.003), and overall survival was significantly increased in the OMX-treated group (25% vs. 85%, P = 0.004). We conclude that OMX is well-tolerated and improves metabolic, hemodynamic, and survival outcomes in an ovine model of controlled hemorrhagic shock.
INHIBITORS OF INORGANIC POLYPHOSPHATE AND NUCLEIC ACIDS ATTENUATE IN VITRO THROMBIN GENERATION IN PLASMA FROM TRAUMA PATIENTS
Authors: MacArthur Taleen A. , Goswami Julie , Navarro Sergio M. , Vappala Sreeparna , La Chanel C. , Yudin Nikoli , Zietlow John , Smith Stephanie A. , Morrissey James H. , Spears Grant M. , Bailey Kent R. , Dong Jing-Fei , Kozar Rosemary A. , Kizhakkedathu Jayachandran N. , Park Myung S.
Published: April 2024

Background:Inorganic polyphosphate (polyP) is a procoagulant polyanion. We assessed the impact of polyP inhibition on thrombin generation after trauma using the novel polyP antagonists, macromolecular polyanion inhibitor 8 (MPI 8), and universal heparin reversal agent 8 (UHRA-8).Methods:Plasma thrombin generation (calibrated automated thrombogram, CAT), in 56 trauma patients and 39 controls +/− MPI 8 and UHRA-8 (50 μg/mL), was expressed as lag time (LT, minutes), peak height (PH, nM), and time to peak (ttPeak, minutes), with change in LT (ΔLT) and change in ttPeak (ΔttPeak) quantified. Results expressed in median and quartiles [Q1, Q3], Wilcoxon matched-pairs testing,P< 0.05 significant.Results:Trauma patients had greater baseline PH than controls (182.9 [121.0, 255.2]; 120.5 [62.1, 174.8],P< 0.001). MPI 8 treatment prolonged LT and ttPeak in trauma (7.20 [5.88, 8.75]; 6.46 [5.45, 8.93],P= 0.020; 11.28 [8.96, 13.14]; 11.00 [8.95, 12.94],P= 0.029) and controls (7.67 [6.67, 10.50]; 6.33 [5.33, 8.00],P< 0.001; 13.33 [11.67, 15.33]; 11.67 [10.33, 13.33],P< 0.001). UHRA-8 treatment prolonged LT and ttPeak and decreased PH in trauma (9.09 [7.45, 11.33]; 6.46 [5.45, 8.93]; 14.02 [11.78, 17.08]; 11.00 [8.95, 12.94]; 117.4 [74.5, 178.6]; 182.9 [121.0, 255.2]) and controls (9.83 [8.00, 12.33]; 6.33 [5.33, 8.00]; 16.67 [14.33, 20.00]; 11.67 [10.33, 13.33]; 55.3 [30.2, 95.9]; 120.5 [62.1, 174.8]), allP< 0.001. Inhibitor effects were greater for controls (greater ΔLT and ΔttPeak for both inhibitors,P< 0.001).Conclusion:PolyP inhibition attenuates thrombin generation, though to a lesser degree in trauma than in controls, suggesting that polyP contributes to accelerated thrombin generation after trauma.
DIMINISHED EXPRESSION OF GLS IN CD4+ T CELLS SERVES AS A PROGNOSTIC INDICATOR ASSOCIATED WITH CUPROPTOSIS IN SEPTIC PATIENTS
Authors: Yang Jiaqi , Chen Ning , Zhao Pengyue , Yang Xingpeng , Li Yuxuan , Fu Ze , Yan Yang , Dong Ning , Li Songyan , Yao Renqi , Du Xiaohui , Yao Yongming
Published: April 2024

Objectives: Sepsis is defined as a life-threatening disease associated with a dysfunctional host immune response. Stratified identification of critically ill patients might significantly improve the survival rate. The present study sought to probe molecular markers associated with cuproptosis in septic patients to aid in stratification and improve prognosis. Methods: We studied expression of cuproptosis-related genes (CRGs) using peripheral blood samples from septic patients. Further classification was made by examining levels of expression of these potential CRGs in patients. Coexpression networks were constructed using the Weighted Gene Coexpression Network Analysis (WGCNA) method to identify crucial prognostic CRGs. Additionally, we utilized immune cell infiltration analysis to further examine the immune status of septic patients with different subtypes and its association with the CRGs. scRNA-seq data were also analyzed to verify expression of key CRGs among specific immune cells. Finally, immunoblotting, flow cytometry, immunofluorescence, and CFSE analysis were used to investigate possible regulatory mechanisms. Results: We classified septic patients based on CRG expression levels and found significant differences in prognosis and gene expression patterns. Three key CRGs that may influence the prognosis of septic patients were identified. A decrease in GLS expression was subsequently verified in Jurkat cells, accompanied by a reduction in O-GlcNAc levels, and chelation of copper by tetrathiomolybdate could not rescue the reduction in GLS and O-GLcNAc levels. Moreover, immoderate chelation of copper was detrimental to mitochondrial function, cell viability, and cell proliferation, as well as the immune status of the host. Conclusion: We have identified novel molecular markers associated with cuproptosis, which could potentially function as diagnostic indicators for septic patients. The reversible nature of the observed alterations in FDX1 and LIAS was demonstrated through copper chelation, whereas the correlation between copper and the observed changes in GLS requires further investigation.
EFFECT OF PULMONARY ARTERY CATHETERIZATION IN PATIENTS WITH NONISCHEMIC CARDIOGENIC SHOCK: A NATIONWIDE ANALYSIS
Authors: Diaz-Arocutipa Carlos , Moreno Guillermo , Gil David Galán , Nieto Sara , Romo Martín , Vicent Lourdes
Published: April 2024

Background: Pulmonary artery catheterization (PAC) has been widely used in critically ill patients, yielding mixed results. Prior studies on cardiogenic shock (CS) predominantly included patients with acute myocardial infarction. This study aims to examine the effect of PAC use in patients with nonischemic CS. Methods: This retrospective cohort study employed data from the National Inpatient Sample database, including weighted hospitalizations of adult patients with nonischemic CS during 2017 to 2019. In-hospital outcomes were compared between groups using inverse probability of treatment weighting. Results: A total of 303,970 patients with nonischemic CS were included, of whom 17.5% received a PAC during their hospitalization. The median age was 67 years (interquartile range: 57–77) and 61% were male. After inverse probability of treatment weighting, patients in the PAC group had significantly lower in-hospital mortality (24.8% vs. 35.3%, P < 0.001), renal replacement therapy (10.7% vs. 12.4%, P = 0.002), in-hospital cardiac arrest (7.1% vs. 9.6%, P < 0.001), and mechanical ventilation (44.6% vs. 50.4%, P < 0.001) compared to non-PAC group. In contrast, the PAC group had higher use of intra-aortic balloon pump (15.4% vs. 3.4%, P < 0.001), percutaneous ventricular assist devices (12.6% vs. 2.6%, P < 0.001), extracorporeal membrane oxygenation (3.9% vs. 2.5%, P < 0.001), and heart transplantation (2.1% vs. 0.4%, P < 0.001). Conclusion: In the real-world setting, invasive hemodynamic monitoring with PAC in patients with nonischemic CS is associated with survival benefits and a reduction in adverse events, including reduced need for renal replacement therapy, mechanical ventilation and risk of in-hospital cardiac arrest.
EFFECTS OF LEVOSIMENDAN ON DIAPHRAGMATIC DYSFUNCTION IN PATIENTS WITH SEPSIS
Authors: Wu Jia-Qian , Wang Ying-Xin , Su Dan , Shao Teng-Hao , Ding Xiao-Xu , Sun Tao , Cui Na , Yu Zhan-Biao
Published: April 2024

Objective: In this study, our aim was to examine the effects of levosimendan on diaphragmatic dysfunction in patients with sepsis, as well as assess its impact on respiratory muscle contractility and the outcome of weaning. Methods: This was a single-blind, randomized, controlled trial. Patients with diaphragmatic dysfunction and failure of spontaneous breathing trials (SBTs) were randomly and equally assigned to the experimental and control groups. The experimental group received levosimendan at a loading dose of 6 μg/kg for 10 min, followed by a continuous infusion at 0.2 μg/kg/min. The control group received an equivalent dose of a placebo. The preadministration and postadministration respiratory mechanics parameters of the patients were recorded. Evaluation of the effect of levosimendan on patients with sepsis-induced diaphragm dysfunction comprised arterial blood gas analysis as well as ultrasound measurements of diaphragm excursion (DE), diaphragm thickness (DT), diaphragm thickening fraction (TFdi), and diaphragm-rapid shallow breathing index (D-RSBI). Results: Forty-four patients were enrolled in the study. We found that postadministration of levosimendan, the patients’ tidal volume (GCSMV) increased, whereas the D-RSBI decreased, and the partial pressure of carbon dioxide (PACO2) decreased when compared to the preadministration levels. Additionally, following levosimendan administration, patients showed increased DE and pressure support (PS) when compared to before administration (1.14 ± 0.177 vs. 1.22 ± 0.170 cm and 0.248 ± 0.03 vs. 0.284 ± 0.06, respectively) and decreased D-RSBI (22.76 ± 6.14 vs. 20.06 ± 6.04, respectively), all of which were statistically significant (P < 0.05). In contrast, in the control group of patients, there were no statistically significant differences in the postadministration levels of DE, TFdi, and D-RSBI as compared to the preadministration period (P > 0.05). Furthermore, in terms of weaning outcomes, we did not find any statistically significant difference in the number of patients in the two groups who eventually underwent weaning (P = 0.545). Conclusion: In this study, we found that levosimendan enhanced diaphragm contractile function. However, further investigations are required to explore its effect on weaning outcomes in patients undergoing mechanical ventilation.
Disparities in Access to Outpatient Surgery Related to Removal of Procedures from Medicare’s Inpatient Only List
Authors: Tsai Thomas C. , Brownlee Sarah A. , Dai Dannie , Soto Mark , Rosenthal Ning , Orav E. John , Frakt Austin B. , Figueroa Jose F.
Published: April 2024

Objective:

We assessed the shift from inpatient to outpatient surgical care related to changes to the Inpatient Only List in 2020 and 2021 compared to 2019.

Summary Background Data:

The extent to which procedures shift from the inpatient to outpatient setting following removal from Medicare’s Inpatient Only List is unknown. Many health systems also encouraged a shift from inpatient to outpatient surgery during the COVID-19 pandemic. Assessing the relative change in outpatient surgical utilization for procedures removed from the Inpatient Only List during COVID-19 would provide empirical data on whether reimbursement policy changes or inpatient capacity needs during the pandemic were more likely to shift care from the inpatient to outpatient setting.

Methods:

We used administrative data from the PINC AI Healthcare Database across 723 hospitals to determine the within-facility relative change in outpatient vs inpatient procedural volume in 2020 and 2021 compared to 2019 using a multivariable conditional fixed-effects Poisson regression model. We also assessed whether outpatient surgical utilization varied by race and ethnicity. Using a multivariable linear probability model, we assessed the absolute change in risk-adjusted 30-day complication, readmission, and mortality rates for inpatient and outpatient surgical procedures.

Results:

In 2020 and 2021 compared to 2019 respectively, there was a 5.3% (95% CI, 1.4% to 9.5%) and 41.3% (95% CI 33.1% to 50.0%) relative increase in outpatient elective procedural volume. Outpatient procedural volume increased most significantly for hip replacement which was removed from the Inpatient Only List in 2020 (increase in outpatient surgical utilization of 589.3% (95% CI, 524.9% to 660.3%)). The shift to outpatient hip replacement procedures was concentrated among White patients; in 2021, hip replacement procedural volume increased by 271.1% (95% CI, 241.2% and 303.7%) for White patients and 29.5% (95% CI, 24.4% and 34.9%) for Black patients compared to 2019 levels. There were no consistent or large changes in 30-day complication, readmission, or mortality risk in 2020 and 2021 compared to 2019.

Conclusion:

There was a modest increase in elective outpatient surgeries and a pronounced increase in outpatient orthopedic surgeries which were removed from the Inpatient Only List during the COVID-19 pandemic. Utilization of outpatient surgical procedures was concentrated among White patients.
Group A Streptococcus isolated in Guyana with reduced susceptibility toβ-lactam antibiotics
Authors: Kalladeen Melissa , Cheddie Paul , Akpaka Patrick Eberechi
Published: April 2024

Introduction: Streptococcus pyogenes (Group A streptococci [GAS]) is the causative agent of pharyngitis and various other syndromes involving cellulitis, streptococcal toxic shock syndrome (STSS) and necrotising fasciitis. Although the prevalence of GAS infections globally remains high, necessitating the widespread use of [[EQUATION]]-lactam antibiotics, GAS has remained largely susceptible to these agents. However, there have been several reports of GAS with reduced susceptibility harbouring mutations in genes for penicillin-binding proteins (PBPs). The objectives of this study were to examine the in vitro -lactam susceptibility patterns of Group A streptococci, determine the prevalence of drug resistance and ascertain whether such resistance could be attributed to mutations in specific PBP genes. 
 
Methods: In this study, we sought to use Sanger sequencing to identify mutations in PBP genes of Streptococcus pyogenes isolated from patients that required inpatient and outpatient care that could confer reduced PBP affinity for penicillin and/or cephalosporin antibiotics. All isolates were screened for susceptibility to penicillin, amoxicillin, and cefazolin using E-test strips. 
 
Results: While there were no documented cases of reduced susceptibility to penicillin or amoxicillin. Thirteen isolates had reduced susceptibility against cefazolin. Examination of pbp1a by Sanger sequencing revealed several isolates with single amino acid substitutions, which could potentially reduce the affinity of PBP 1A for cefazolin and possibly other first-generation cephalosporins.
 
Conclusion: Penicillin and penicillin-derived antibiotics remain effective treatment options for GAS infections, but active surveillance is needed to monitor for changes to susceptibility patterns against these and other antibiotics and understand the genetic mechanisms contributing to them.
Safety of RSV Vaccine among Pregnant Individuals: A Real-World Pharmacovigilance Study Using Vaccine Adverse Event Reporting System
Authors: Alami Abdallah , Perez-Lloret Santiago , Mattison Donald R.
Published: April 2024

Objectives

To describe the post-marketing safety of RSVPreF among pregnant individuals.

Design

This case series study analyzed adverse event (AE) reports submitted to the U.S. Food and Drug Administration’s Vaccine Adverse Event Reporting System (VAERS) database following RSVPreF immunization from September 1, 2023, to February 23, 2024.

Setting

VAERS, as a national spontaneous vaccine safety surveillance system, provides insights into the safety profile of the RSVPreF vaccine in a real-world setting.

Participants

Surveillance data included all AE reports submitted to VAERS for pregnant individuals following vaccination.

Exposure

Receipt of RSVPreF vaccine among pregnant individuals in the U.S.

Primary and secondary outcome measures

Descriptive statistics assessed all AE reports with RSVPreF, including frequency, gestational age at vaccination, time to AE onset, and serious report proportions. The Bayesian Confidence Propagation Neural Network (BCPNN) was utilized, estimating the information component (IC) to identify disproportionate reporting of RSVPreF–event pairs.

Results

VAERS received 77 reports pertained to RSVPreF vaccination in pregnant individuals, with 42 (54.55%) classified as serious. The most reported non-pregnancy-specific AEs were headache, injection site erythema, and injection site pain. Preterm birth was the most frequently reported pregnancy-specific AE, followed by preterm premature rupture of membranes, cesarean section, cervical dilatation, and hemorrhage during pregnancy. The median time from immunization to reported preterm birth was 3 days, with two-thirds of cases within a week. Disproportionality analysis indicated a significant signal for various AEs, particularly highlighting preterm birth with an IC of 2.18 (95%CI, 1.54-2.63), suggesting that reports of preterm birth associated with RSVPreF vaccination occurred more frequently than statistically expected.

Conclusions

While reported AEs were generally consistent with the safety profile observed in prelicensure studies, this study highlights ongoing concern about preterm birth among pregnant individuals following RSVPreF vaccination. Comprehensive longitudinal follow-up, including prospective pregnancy registries and infant follow-up studies is urgently required.
Exploring the Potential of Structure-Based Deep Learning Approaches for T cell Receptor Design
Authors: Ribeiro-Filho Helder V. , Jara Gabriel E. , Guerra João V. S. , Cheung Melyssa , Felbinger Nathaniel R. , Pereira José G. C. , Pierce Brian G. , Lopes-de-Oliveira Paulo S.
Published: April 2024

Deep learning methods, trained on the increasing set of available protein 3D structures and sequences, have substantially impacted the protein modeling and design field. These advancements have facilitated the creation of novel proteins, or the optimization of existing ones designed for specific functions, such as binding a target protein. Despite the demonstrated potential of such approaches in designing general protein binders, their application in designing immunotherapeutics remains relatively unexplored. A relevant application is the design of T cell receptors (TCRs). Given the crucial role of T cells in mediating immune responses, redirecting these cells to tumor or infected target cells through the engineering of TCRs has shown promising results in treating diseases, especially cancer. However, the computational design of TCR interactions presents challenges for current physics-based methods, particularly due to the unique natural characteristics of these interfaces, such as low affinity and cross-reactivity. For this reason, in this study, we explored the potential of two structure-based deep learning protein design methods, ProteinMPNN and ESM-IF, in designing fixed-backbone TCRs for binding target antigenic peptides presented by the MHC through different design scenarios. To evaluate TCR designs, we employed a comprehensive set of sequence- and structure-based metrics, highlighting the benefits of these methods in comparison to classical physics-based design methods and identifying deficiencies for improvement.
Combined thermodynamic and time-resolved structural analysis of interactions between AP2 and biomimetic plasma membranes provides insights into clathrin-mediated endocytosis
Authors: Maestro Armando , Zaccai Nathan R. , Gonzalez-Martinez J.F. , Sanchez-Puga P. , Tajuelo J. , Rubio M. A. , Santamaria Andreas , Carrascosa-Tejedor J. , Pereira D. , Marín-Montesinos I. , Gutfreund P. , Campbell Richard , Kotar J. , Kelly Bernard T. , Cicuta Pietro , Owen David J.
Published: April 2024

Clathrin mediated endocytosis (CME) is the main mechanism for swift and selective uptake of proteins into eukaryotic cells. CME is initiated by recruitment to the plasma membrane (PM) of the adaptor protein AP2, which recognizes the PM-associated lipid PtdIns(4,5)P2, as well as the protein cargo to be internalized. Nonetheless, many aspects of this process remain unclear due to their in vivo complexity. Here, a thermodynamic and time-resolved structural analysis of AP2 binding to different biomimetic PM was undertaken under physiological conditions using a combination of neutron reflectometry, interfacial tensiometry and rheology, and atomic force microscopy. The resultant in vitro data replicated previous in vivo observations, as well as yielded biophysical insights into normal and aborted CME. The presence of cargo may not be pivotal for the “activating” conformational change of AP2. However, the presence of cargo extends AP2’s residence time on the membrane surface, due to slower on- and off-rates, thereby tentatively giving sufficient time for CME to proceed fully. Moreover, upon interaction with AP2, phospholipid lateral diffusion decreases markedly, inducing a gel phase attributed to creating a percolated network involving AP2 on the membrane, which could potentially serve as a mechanism for modulating subsequent clathrin binding.
Varying phylogenetic signal in susceptibility to four bacterial pathogens across species of Drosophilidae
Authors: Sun Hongbo , Hanson Mark A. , Walsh Sarah K. , Imrie Ryan M. , Raymond Ben , Longdon Ben
Published: April 2024

Bacterial infections are one of the major sources threatening public health. Pathogen host shifts – where a pathogen jumps from one host species to another – are important sources of emerging infectious diseases. However, compared to viruses, we know relatively little about the factors that determine whether a bacteria can infect a novel host, such as how host phylogenetics constrains variation in pathogen-host range and the link between host phylogeny and the infectivity and virulence of a pathogen. Here, we experimentally examined susceptibility to bacterial infections using a panel of 36 Drosophilidae species and four pathogens (Providencia rettgeri,Pseudomonas entomophila,Enterococcus faecalis,Staphylococcus aureus). The outcomes of infection differed greatly among pathogens and across host species. The host phylogeny explains a considerable amount of variation in susceptibility, with the greatest phylogenetic signal forP. rettgeriinfection, explaining 94% of the variation in mortality. Positive correlations were observed between mortality and bacterial load for three out of the four pathogens. Correlations in susceptibility between the four pathogens were positive but largely non-significant, suggesting susceptibility is mostly pathogen-specific. These results suggest that susceptibility to bacterial pathogens may be predicted by the host phylogeny, but the effect may vary in magnitude between different bacteria.
Spatiotemporal dynamics revealed the dark water community of giant virus from a deep freshwater lake
Authors: Zhang Liwen , Meng Lingjie , Fang Yue , Ogata Hiroyuki , Okazaki Yusuke
Published: April 2024

Giant viruses significantly regulate the ecological dynamics of diverse ecosystems. Although metagenomics has expanded our understanding of their diversity and ecological roles played in marine environments, little is known about giant viruses of freshwater ecosystems. Most previous studies have employed short-read sequencing and therefore resulted in fragmented genomes, hampering accurate assessment of genetic diversity. We sought to bridge this knowledge gap and overcome previous technical limitations. We subjected spatiotemporal (2 depths × 12 months) samples from Lake Biwa to metagenome-assembled genome reconstruction enhanced by long-read metagenomics. This yielded 294 giant virus metagenome-assembled genomes. Of these, 285 included previously unknown species in five orders of nucleocytoviruses and the first representatives of freshwater mirusviruses, which exhibited marked divergence between freshwater- and marine-derived lineages. Notably, 42 (14.3%) genomes were composed of single contigs with completeness values >90%, demonstrating the good performance of our long-read metagenomic assembly. Giant viruses were partitioned across water depths, with most species specific to either the sunlit epilimnion or the dark hypolimnion. Epilimnion-specific members tended to be opportunistic and to exhibit short and intense abundance peaks, in line with the fact that they regulate the surface algal blooms. During the spring bloom, mirusviruses and members of three nucleocytovirus families were among the most abundant giant viruses. In contrast, hypolimnion-specific ones including algaviruses and mirusviruses were typically more persistent in the hypolimnion throughout the water-stratified period, suggesting that they infect hosts specific to the hypolimnion and play previously unexplored ecological roles in dark water-specific microbial ecosystems.
It is hard to be small: Inbreeding depression depends on the body size in a threatened songbird
Authors: Kubacka Justyna , Arantes Larissa S. , Herdegen-Radwan Magdalena , Osiejuk Tomasz S. , Sparmann Sarah , Mazzoni Camila J.
Published: April 2024

While inbreeding is known to affect individual fitness and thus population extinction risk, studies have under-represented non-model species of conservation concern, and rarely sought conditionality of inbreeding depression. Here, using SNPs identified with RAD-seq, we determined inbreeding depression in a threatened bird, the aquatic warblerAcrocephalus paludicola, and whether its magnitude depends on phenotypic and environmental factors. We found that the inbreeding coefficient (F) of adults with small tarsi was negatively associated with the seasonal breeding success (in males) and clutch size (in females), with the respective decrease in fitness in the most inbred relative to the least inbred individuals of ~89% and ~12%. In contrast, in adult males, for the average tarsus, wing and mass, support was low forFto be related to the long-term return rate to breeding grounds. For mean phenotypic covariates and male density, we also found low evidence thatFis associated with the annual breeding success. Likewise, there was little support that motherFis related to egg hatch success and nestling survival, and – for average phenotypic traits, rainfall, temperature and nest density, and accounting for breeding peak – to clutch and fledged brood sizes. For nestlings, animal models showed that F is more negatively related to tarsus under higher temperatures and its effect varies by study year. However, for average brood size, temperature, rainfall and prey abundance, and when controlling for nestling sex, breeding peak and motherF, evidence for nestling F and tarsus association was weak. We conclude that (1) inbreeding depression on fitness components is stronger in smaller-bodied individuals, (2) considering interaction with phenotypic and environmental variables enables more accurate estimation of inbreeding depression, and (3) the inbreeding depression estimates will inform extinction risk analysis and conservation actions for the aquatic warbler.
The newSH3_Tdomain increases the structural and functional variability among SH3b-like CBDs from staphylococcal phage endolysins
Authors: Vázquez Roberto , Gutiérrez Diana , Grimon Dennis , Fernández Lucía , García Pilar , Rodríguez Ana , Briers Yves
Published: April 2024

Endolysins, proteins encoded by phages to lyse their hosts and release their progeny, have evolved to adapt to the structural features of each host. The endolysins fromStaphylococcus-infecting phages typically feature complex architectures with two enzymatically active domains (EADs) and one cell wall-binding domain (CBD) belonging to the bacterial SH3 (SH3b) superfamily. This study focuses on three SH3b-like CBDs from exemplary staphylococcal phage endolysins (LysRODI, LysC1C, and LysIPLA5) that were structurally and functionally characterized. While RODI_CBD and C1C_CBD were assigned to the well-knownSH3_5family, a new family,SH3b_T, was identified using the CBD from LysIPLA5 as a model. GFP-fused CBDs were created to assess their differential binding to a collection of staphylococcal strains. IPLA5_CBD showed enhanced binding toStaphylococcus epidermidis, while RODI_CBD and C1C_CBD exhibited distinct binding profiles, with RODI_CBD targetingStaphylococcus aureusspecifically and C1C_CBD displaying broad binding. Sequence comparisons suggested that a few differences in key amino acids could be responsible for the latter binding difference. The CBDs modulated the activity spectrum of synthetic EAD-CBD combinations in accordance with the previous binding profiles, but in a manner that was also dependent on the EAD present in the fusion protein. These results serve as a context for the diversity and versatility of SH3b domains in staphylococcal endolysins, providing insights on how (i) the CBDs from this superfamily have diverged to adapt to diverse bacterial ligands in spite of sharing a common fold; and (ii) the evolution of specificity relies on the EAD-CBD combination rather than solely the CBD.

IMPORTANCE

Clinical management of bacterial infections is nowadays compromised by the rise in antimicrobial resistance. The development of new antimicrobial therapies with diverse modes of action is therefore of pivotal importance to complement the current standard of care. Phage endolysins are a new class of antibacterial agents based on rapid peptidoglycan degradation. The natural reservoir of phage endolysins offers a practically infinite diversity. This works reveals a broadly spread but still unknown phage endolysin domain targeting staphylococci while providing structural-functional insights that are paramount to understand the evolution of endolysins and how they can be applied as an antimicrobial.
The invasion phenotypes of glioblastoma depend on plastic and reprogrammable cell states
Authors: Doroszko Milena , Stockgard Rebecka , Yildirim Irem , Ballester Bravo Mar , Millner Thomas O , Kundu Soumi , Heinold Josephine , Elgendy Ramy , Berglund Maria , Elfineh Ludmila , Krona Cecilia , Marino Silvia , Larsson Ida , Nelander Sven
Published: April 2024

Glioblastoma (GBM), the most common brain cancer in adults, is characterized by rapid local invasion, along diverse routes such as infiltration of white matter tracts and penetration of perivascular spaces. We investigate the hypothesis that GBM invasion routes correlate with the transcriptional states of individual cells and identify route-specific master regulator genes. Utilizing patient-derived GBM xenograft models, we integrate single-cell transcriptomics and spatial proteomics, revealing that mesenchymal and oligodendrocyte progenitor-like GBM cells migrate perivascularly, while neural progenitor and astrocyte-like GBM cells invade diffusively. Computational reconstruction identifies ANXA1 as a perivascular invasion driver and lineage-restricted transcription factors RFX4 and HOPX as drivers of diffuse invasion, predictive of patient survival. Genetic ablation of these genes alters invasion phenotypes and extends survival in xenografted mice, clarifying the role of cell states in GBM invasion, and highlighting potential therapeutic targets for selective invasion route targeting in GBM patients.
Nonlinear progression during the occult transition establishes cancer lethality
Authors: Ginzel Joshua D. , Chapman Henry , Sills Joelle E. , Allen Edwin J. , Barak Lawrence S. , Cardiff Robert D. , Borowsky Alexander D. , Lyerly H. Kim , Rogers Bruce W. , Snyder Joshua C.
Published: April 2024

Cancer screening is based upon a linear model of neoplastic growth and malignant progression. Yet, historical observations suggest that malignant progression is uncoupled from growth which may explain the paradoxical increase in early-stage breast cancer detection without a dramatic reduction in metastatic burden. Here we lineage trace millions of genetically transformed field cells and thousands of screen detectable and symptomatic tumors using a cancer rainbow mouse model of HER2+ breast cancer. Transition rates from field cell to screen detectable tumor and then to symptomatic tumors were estimated from a dynamical model of tumor development. Field cells are orders of magnitude less likely to transition to a screen detectable tumor than the subsequent transition of a screen detectable tumor to a symptomatic tumor. Our model supports a critical occult transition in tumor development during which time a transformed cell becomes abona fideneoplasm. Lineage tracing and test-by-transplantation reveals that nonlinear progression during or prior to the occult transition gives rise to nascent lethal cancers at screen detection. Simulations illustrate how occult transition rates are a critical determinant of tumor growth and malignancy in the lifetime of a host. Our data provides direct experimental evidence that cancers can deviate from the predictable linear progression model foundational to current screening paradigms
TheChlamydiaeffector IncE employs two short linear motifs to reprogram host vesicle trafficking
Authors: Pha Khavong , Mirrashidi Katherine , Sherry Jessica , Tran Cuong Joseph , Herrera Clara M. , McMahon Eleanor , Elwell Cherilyn A. , Engel Joanne N.
Published: April 2024

Chlamydia trachomatis,a leading cause of bacteria sexually transmitted infections, creates a specialized intracellular replicative niche by translocation and insertion of a diverse array of effectors (Incs) into the inclusion membrane. Here, we characterize IncE, a multi-functional Inc that encodes two non-overlapping short linear motifs (SLiMs) within its short cytosolic C-terminus. The proximal SLiM mimics an R-SNARE motif to recruit syntaxin (STX) 7 and 12-containing vesicles to the inclusion. The distal SLiM mimics the Sorting Nexin (SNX) 5 and 6 cargo binding site to recruit SNX6-containing vesicles to the inclusion. By simultaneously binding to two distinct vesicle classes, IncE reprograms host cell trafficking to promote the formation of a class of hybrid vesicles at the inclusion that are required forC. trachomatisintracellular development. Our work suggests that Incs may have evolved SLiMs to facilitate rapid evolution in a limited protein space to disrupt host cell processes.