bluuebunny/crossref_metadata_2025 huggingface dataset:
Concurrent Atezolizumab Plus Bevacizumab and High-Dose External Beam Radiotherapy for Highly Advanced Hepatocellular Carcinoma
Authors: Su Chung-Wei , Teng Wei , Shen Eric Yi-Liang , Huang Bing-Shen , Lin Po-Ting , Hou Ming-Mo , Wu Tsung-Han , Tsan Din-Li , Hsieh Chia-Hsun , Wang Ching-Ting , Chai Pei-Mei , Lin Chun-Yen , Lin Shi-Ming , Lin Chen-Chun
Published: March 2024

Background

Atezolizumab plus bevacizumab (atezo-bev) has been recommended for advanced hepatocellular carcinoma (HCC). High-dose external beam radiotherapy (RT) is recognized for its excellent local tumor control. The efficacy and safety of concurrent atezo-bev with RT for highly advanced HCC has been minimally explored.

Methods

In this preliminary retrospective study, we assessed patients with highly advanced HCC, characterized by Vp4 portal vein thrombosis or tumors exceeding 50% of liver volume, who received concurrent atezo-bev and RT (group A). Group A included 13 patients who received proton radiation at a dose of 72.6 GyE in 22 fractions, and one patient who received photon radiation at a dose of 54 Gy in 18 fractions. This group was compared with 34 similar patients treated atezo-bev alone as a control (group B). The primary objectives were to evaluate the objective response rate (ORR), overall survival (OS), and safety.

Results

Baseline characteristics were similar between groups, except for a higher incidence of Vp4 portal vein thrombosis in group A (78.6% vs. 21.4%, P = .05). Group A achieved a higher ORR (50.0% vs. 11.8%, P < .01) and a longer OS (not reached vs. 5.5 months, P = .01) after a median follow-up of 5.2 months. Multivariate analysis indicated that concurrent RT independently favored longer OS (hazard ratio: 0.18; 95% CI, 0.05-0.63, P < .01). Group A did not increase any grade adverse events (78.6% vs. 58.8%, P = .19) or severe adverse events of grade ≥ 3 (14.3% vs. 14.7%, P = .97) compared to group B.

Conclusions

The concurrent high-dose external beam radiotherapy appears to safely enhance the effectiveness of atezolizumab plus bevacizumab for highly advanced patients with HCC. Further studies are warranted to confirm these findings.
Phytohormonal regulation determines the organization pattern of shoot aerenchyma in greater duckweed (Spirodela polyrhiza)
Authors: Kim Min , Hyeon Do Young , Kim Kyungyoon , Hwang Daehee , Lee Yuree
Published: March 2024

Airspace or aerenchyma is crucial for plant development and acclimation to stresses such as hypoxia, drought, and nutritional deficiency. Although ethylene-mediated signaling cascades are known to regulate aerenchyma formation in stems and roots under hypoxic conditions, the precise mechanisms remain unclear. Moreover, the cellular dynamics underlying airspace formation in shoots are poorly understood. We investigated the stage-dependent structural dynamics of shoot aerenchyma in greater duckweed (Spirodela polyrhiza), a fast-growing aquatic herb with well-developed aerenchyma in its floating fronds. Using X-ray micro-computed tomography and histological analysis, we showed that the spatial framework of aerenchyma is established before frond volume increases, driven by cell division and expansion. The substomatal cavity connecting aerenchyma to stomata formed via programmed cell death (PCD) and was closely associated with guard cell development. Additionally, transcriptome analysis and pharmacological studies revealed that the organization of aerenchyma in greater duckweed is determined by the interplay between PCD and proliferation. This balance is governed by spatiotemporal regulation of phytohormone signaling involving ethylene, abscisic acid, and salicylic acid. Overall, our study reveals the structural dynamics and phytohormonal regulation underlying aerenchyma development in duckweed, improving our understanding of how plants establish distinct architectural arrangements. These insights hold the potential for wide-ranging application, not only in comprehending aerenchyma formation across various plant species but also in understanding how airspaces are formed within the leaves of terrestrial plants.
Effect of an interdisciplinary inpatient program for patients with complex regional pain syndrome in reducing disease activity—a single-center prospective cohort study
Authors: Schneider Stephanie , Wertli Maria M , Henzi Anna , Hebeisen Monika , Brunner Florian
Published: March 2024

Objective

The aim of this study was to evaluate the benefit of inpatient treatment in reducing disease activity in patients with complex regional pain syndrome (CRPS) who have exhausted outpatient options. Furthermore, the study sought to identify patient-related outcome variables that predict a reduction in disease activity.

Methods

The primary outcome was disease severity (CRPS Severity Score, range 0-16 points). Secondary outcomes included depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and the ability to participate in social roles and activities, all of which were assessed using the PROMIS-29. Furthermore, pain catastrophizing, neuropathic pain, quality of life, pain self-efficacy, medication intake, and the patient's global impression of change were examined in accordance with current international agreed recommendations, assessed at discharge, 3-month, and 6-month post-discharge. Mixed-effects models were conducted to identify baseline variables associated with CRPS severity.

Results

Twenty-five patients completed the program (mean age 49.28 [SD 11.23] years, 92% females, mean symptom duration 8.5 [SD 6.5] months). Results showed a significant reduction between baseline and discharge of disease activity (CSS −2.36, P < .0001), pain (PROMIS-29 pain −0.88, P = .005), and emotional function (PROMIS-29 depression −5.05, P < .001; fatigue −4.63, P = .002). Moderate evidence for a reduction between baseline and discharge could be observed for pain interference (+2.27, P = .05), social participation (PROMIS-29 + 1.93, P = .05), anxiety (PROMIS-29 −3.32, P = .02) and physical function (PROMIS-29 + 1.3, P = .03). On discharge, 92% of patients (23 of 25) reported improvement in their overall condition. In the follow-up period, medication intake could be reduced after 3 (MQS −8.22, P = .002) and 6 months (MQS −8.69, P = .001), and there was further improvement in social participation after 3 months (PROMIS-29 + 1.72, 0.03) and sleep after 6 months (PROMIS-29 + 2.38, 0.008). In the mixed models, it was demonstrated that patients experiencing less pain at baseline also exhibited lower disease activity.

Conclusion

The results of this study confirm that inpatient interdisciplinary treatment of CRPS patients improves disease activity, pain, physical function, emotional function, and social participation. Most improvements were maintained for up to 6 months after discharge. The majority of patients reported that their overall condition had improved during the study period.
Regional European genetic ancestry predicts type I interferon level and risk of severe viral infection
Authors: Nln I , Shum J , Ghodke-Puranik Y , Tipon R , Triese D , Amin S , Makol A , Osborn T , Chowdhary V , Thanarajasingam U , Muskardin T L W , Oke V , Gunnarsson I , Zickert A , Zervou M I , Boumpas D T , Svenungsson E , Goulielmos G N , Niewold T B
Published: March 2024

Background

Viral infection outcomes vary widely between individuals, ranging from mild symptoms to severe organ failure and death, and it is clear that host genetic factors play a role in this variability. Type I interferon (IFN) is a critical anti-viral cytokine, and we have previously noted differences in type I IFN levels between world populations.

Methods

In this study, we investigate the interrelationship between regional European genetic ancestry, type I IFN levels and severe viral infection outcomes.

Results

In cohorts of European ancestry lupus patients living in Europe, we noted higher IFN in the Northwestern populations as compared to Southeastern populations. In an independent cohort of European ancestry lupus patients from the USA with varying proportional regional European genetic admixture, we observed the same Northwest vs. Southeast European ancestry IFN gradient. We developed a model to predict type I IFN level based on regional European ancestry (Area under the curve (AUC) = 0.73, P = 6.1e-6). Examining large databases containing serious viral outcomes data, we found that lower predicted IFN in the corresponding European country was significantly correlated with increased viral infection fatality rate, including Coronavirus Disease 2019 (COVID-19), viral hepatitis and HIV [correlation coefficients: −0.79 (P = 4e-2), −0.94 (P = 6e-3) and −0.96 (P = 8e-2), respectively].

Conclusions

This association between predicted type I IFN level and viral outcome severity suggests a potential causal relationship, as greater intrinsic type I IFN is beneficial in host defense against viruses. Genetic testing could provide insight into individual and population level risk of fatality due to viruses prior to infection, across a wide range of viral pathogens.
Daptomycin-induced eosinophilic pneumonia
Authors: Hassett Michael R.
Published: March 2024

Daptomycin-induced eosinophilic pneumonia (DIEP) is a rare complication of daptomycin use. Manifestations most commonly include fever, hypoxia, dyspnea, cough, eosinophilia, and lung changes on radiographs and CT. Patients typically have had recent daptomycin exposure and develop fever, dyspnea, infiltrates on chest radiograph, more than 25% eosinophils on bronchoalveolar lavage, and improvement of symptoms after withdrawal of daptomycin. Treatment includes discontinuation of daptomycin, corticosteroids, and supportive measures such as supplemental oxygen. Clinicians should have a high index of suspicion for DIEP in patients who develop new onset of pulmonary and systemic signs and symptoms after initiation of daptomycin.
Heart failure related to contemporary breast cancer treatment
Authors: Durkin Megan , DeJesus Neisha
Published: March 2024

This article addresses cardiotoxicity in patients with breast cancer who are treated with anthracyclines and/or anti-human epidermal growth factor 2 (HER2) therapy, namely doxorubicin and trastuzumab. Development of concise clinical guidelines for chemotherapy-induced heart failure is ongoing. Through identification of specific risk factors and clinical predictors of cardiotoxicity, clinicians are able to better understand and define effective monitoring strategies and optimize patient care. Close cardiac monitoring is recommended for patients throughout treatment with anthracyclines and anti-HER2 therapy. Pretreatment risk assessment with echocardiography and evaluation of cardiovascular risk factors aid in predicting the development of left ventricular (LV) dysfunction. Further clinical trials are needed to increase understanding and optimize treatment guidelines for LV dysfunction in patients taking anthracyclines or anti-HER2 therapy.
An update on treatment and outcomes for alcoholic hepatitis
Authors: Brakebush Elizabeth
Published: March 2024

Alcoholic hepatitis is a form of inflammation of the liver caused by alcohol use. Data on the best treatment are conflicting. Treatment guidelines include the use of prednisolone and supportive care, although this is controversial. This article reviews the guidelines for treating alcoholic hepatitis and current recommendations.
GLP-1 receptor agonists
Authors: Clark LaDonna
Published: March 2024

Type 2 diabetes mellitus (T2DM) is a chronic medical condition affecting millions of individuals worldwide. The burden of disease is significant, as demonstrated by high morbidity and mortality and billions of healthcare dollars spent. The pathophysiology of T2DM is complex, with eight primary deficits. In recent years, an increased focus has been placed on incretin hormones, such as glucagon-like peptide-1 (GLP-1) for its glucose-lowering benefits. Several FDA-approved short-acting and long-acting GLP-1 receptor agonists (GLP-1 RAs) are available in the United States for the treatment of T2DM. These are liraglutide, exenatide, dulaglutide, and semaglutide, all administered via subcutaneous injection. Semaglutide is also available in an oral formulation. A newer dual glucose-dependent insulinotropic peptide (GIP) and GLP-1 RA, tirzepatide, is available as a subcutaneous injectable. In addition to improving glycemic control, GLP-1 RAs have been shown to lower total body weight, BP, and cholesterol as well as to improve renal function and beta-cell proliferation. These agents should be considered in every patient with T2DM due to their substantial clinical benefits and potential to help reduce disease burden.
Caloric restriction, Sirtuins, and cardiovascular diseases
Authors: Wei Ziyu , Yang Bo , Wang Huiyu , Lv Shuangjie , Chen Houzao , Liu Depei
Published: March 2024

Caloric restriction (CR) is a well-established dietary intervention known to extend healthy lifespan and exert positive effects on aging-related diseases, including cardiovascular conditions. Sirtuins, a family of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, have emerged as key regulators of cellular metabolism, stress responses, and the aging process, serving as energy status sensors in response to CR. However, the mechanism through which CR regulates Sirtuin function to ameliorate cardiovascular disease remains unclear. This review not only provided an overview of recent research investigating the interplay between Sirtuins and CR, specifically focusing on their potential implications for cardiovascular health, but also provided a comprehensive summary of the benefits of CR for the cardiovascular system mediated directly via Sirtuins. CR has also been shown to have considerable impact on specific metabolic organs, leading to the production of small molecules that enter systemic circulation and subsequently regulate Sirtuin activity within the cardiovascular system. The direct and indirect effects of CR offer a potential mechanism for Sirtuin modulation and subsequent cardiovascular protection. Understanding the interplay between CR and Sirtuins will provide new insights for the development of interventions to prevent and treat cardiovascular diseases.
The Extended Chest Wall Perforator Flap: Expanding the Indication for Partial Breast Reconstruction
Authors: Rankin Adeline C. , Almalki Hend , Mirshekar-Syahkal Bahar , Hussien Maged I.
Published: March 2024

Background:

The intercostal artery perforator flap has traditionally been used to reconstruct small or moderate-sized single defects in the lateral or lower medial breast during breast-conserving surgery. We report a modification of the intercostal artery perforator flap that allows for reconstruction of larger breast tumors than previously described flap designs.

Methods:

A retrospective study of breast cancer patients undergoing breast-conserving surgery and immediate partial breast reconstruction with an extended chest wall perforator flap. Primary outcomes were successful tumor excision, adequate radial margins, postoperative complications, and delays to adjuvant radiotherapy.

Results:

Thirty patients were included. Mean radiological tumor size was 27 mm (11–56 mm) and excision volume, 123 cm3 (18–255 cm3). All tumors had satisfactory excision margins, and no patient required further surgery for re-excision. In the early postoperative period, one patient required radiological drainage of seroma, and one returned to theater for debridement of fat necrosis affecting the flap. Ten other patients were managed on an outpatient basis for minor wound complications. All patients were followed up annually for 5 years. No patients had a delay to adjuvant treatment or required revisional procedures for cosmesis.

Conclusions:

The modified chest wall perforator flap allows for breast conservation for larger tumors from all quadrants of the breast, including centrally located tumors and reconstruction of the axillary defect following lymph node clearance. The length of the flap allows for the use of multiple perforators in the pedicle area and freedom of the flap to reach the defects. This can be performed with low morbidity and no delay to adjuvant radiotherapy.
Right ventricular scalloping index as cardiac magnetic resonance-derived marker for diagnosis of arrhythmogenic right ventricular cardiomyopathy
Authors: Huang Ko-Ying , Chung Fa-Po , Guo Chao-Yu , Chiu Jui-Han , Kuo Ling , Lee Ying-Chi , Weng Ching-Yao , Chang Ying-Yueh , Lin Yenn-Jiang , Chen Chun-Ku
Published: March 2024

Background:

The cardiac magnetic resonance (CMR) evaluation of right ventricular (RV) morphologic abnormalities in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) is subjective. Here, we aimed to use a quantitative index, the right ventricular scalloping index (RVSI), to standardize the measurement of RV free wall scalloping and aid in the imaging diagnosis.

Methods:

We retrospectively included 15 patients with definite ARVC and 45 age- and sex-matched patients with idiopathic right ventricular outflow tract ventricular arrhythmia (RVOT-VA) as controls. The RVSI was measured from cine images on four-chamber view to evaluate its ability to distinguish between ARVC and RVOT-VA patients. Other cardiac functional parameters including strain analysis were also performed.

Results:

The RVSI was significantly higher in the ARVC than RVOT-VA group (1.56 ± 0.23 vs 1.30 ± 0.08, p < 0.001). The diagnostic performance of the RVSI was superior to the RV global longitudinal, circumferential, and radial strains, RV ejection fraction, and RV end-diastolic volume index. The RVSI demonstrated high intraobserver and interobserver reliability (intraclass correlation coefficient, 0.94 and 0.96, respectively). RVSI was a strong discriminator between ARVC and RVOT-VA patients (area under curve [AUC], 0.91; 95% CI, 0.82-0.99). A cutoff value of RVSI ≥1.49 provided an accuracy of 90.0%, specificity of 97.8%, sensitivity of 66.7%, positive predictive value (PPV) of 90.9%, and a negative predictive value (NPV) of 89.8%. In a multivariable analysis, a family history of ARVC or sudden cardiac death (odds ratio, 38.71; 95% CI, 1.48-1011.05; p = 0.028) and an RVSI ≥1.49 (odds ratio, 64.72; 95% CI, 4.58-914.63; p = 0.002) remained predictive of definite ARVC.

Conclusion:

RVSI is a quantitative method with good performance for the diagnosis of definite ARVC.
Macrophage Polarization and Crosstalk between Macrophages and Other Cells in Hidradenitis Suppurativa
Authors: Zhang Qiujing , Feng Yibo , Chen Xiang , Mo Xiaohui , Wu Qiong , Ju Qiang
Published: March 2024

Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic inflammatory disease characterized by the development of inflammatory nodules, abscesses, and pus-discharging tunnels in areas such as the axillary, inguinal, gluteal, and perianal regions. The pathogenesis of HS remains unclear, but it is being increasingly recognized to rely on the dysregulation of inflammatory responses. Central to this process are macrophages, which have emerged as key players in the inflammatory milieu of HS. These cells orchestrate inflammation via polarization and significantly influence the functions of neighboring cells. This review briefly describes macrophage polarization and crosstalk between macrophages and other cells in patients with HS with the aim of providing new therapeutic strategies for the clinical management of HS.
Standardized order set for the management of infective endocarditis
Authors: Murphy Kerneisha , Eiswirth Emily
Published: March 2024

Background:

Infective endocarditis (IE) is a potentially life-threatening infection that affects the inner lining of the heart, particularly the heart valves. Patients with preexisting heart conditions, damaged heart valves, or a history of intravenous drug use are at a higher risk of acquiring IE.

Local problem:

A rural acute care facility reported that 68.75% of patients who had a methicillin-resistant Staphylococcus aureus infection were diagnosed with IE. Review of medical records showed that 65% of patients with IE did not have antibiotic start/stop dates and 51% were discharged before the 6-week completion date.

Methods:

The quality-improvement project used a pretest and posttest design. An order set was created based on evidence-based guidelines to assist with the management of patients with IE. The order set included administering intravenous (IV) antibiotics for a minimum of 6 weeks for patients with IE and included a set of recommended weekly follow-up laboratory tests.

Interventions:

An order set with the standard of care and reminders in the electronic health records (EHRs) were implemented for the management of IE, including antibiotic start and stop dates and weekly follow-up labs.

Results:

After implementation, there was an improvement in the completion of IV antibiotics, documentation of start/stop dates for IV antibiotics, and completion of recommended laboratory tests.

Conclusions:

An order set with the standard of care and reminders in the EHR reduced variations in care and improved patient outcomes by ensuring that all providers were following the same evidence-based guidelines for the management of IE.
Tensor Tympani and Stapedial Tendon Reconstruction for Postoperative Hyperacusis after Tendon Lysis for Middle Ear Myoclonus
Authors: Khandalavala Karl R. , Dornhoffer James R. , Poling Gayla L. , Driscoll Colin L.
Published: March 2024

Objective

To present a method for repair of the stapedial and tensor tympani tendons in a patient with hyperacusis after a tendon lysis procedure.

Patients

A 71-year-old professional musician who presented to clinic with debilitating hyperacusis following a tensor tympani and stapedial tendon lysis procedure to treat middle ear myoclonus.

Interventions

A novel procedure for reapproximation of the tensor tympani and stapedial tendons into their native insertion points using periosteal grafts and nitinol wire.

Main Outcomes Measures

Stapedial reflex measurements, uncomfortable loudness level, and subjective patient experience.

Results

Postoperatively, the patient had objective improvement in hyperacusis with return of acoustic reflexes in the affected ear and durable improvements in their frequency-specific uncomfortable loudness levels.

Conclusions

This case describes the debilitating complication of hyperacusis following tendon lysis and highlights the importance of maximizing behavioral and medical measures prior to undergoing surgical intervention for middle ear myoclonus.
Morphology of the Dorsal Pancreatic Artery and Its Oncological Significance in Pancreatic Cancer
Authors: Kyuno Takahiro , Makino Isamu , Kitagawa Hirohisa , Terakawa Hirofumi , Gabata Ryosuke , Tokoro Tomokazu , Takada Satoshi , Okazaki Mitsuyoshi , Nakanuma Shinichi , Ohta Tetsuo , Yagi Shintaro
Published: March 2024

Objectives

Although the dorsal pancreatic artery (DPA) is an important artery that supplies the pancreas, its morphology has not been sufficiently studied. We investigated the morphology of the DPA and the progression of pancreatic cancer along this vessel.

Materials and Methods

Overall, 142 patients with pancreatic cancer who underwent surgical resection at Kanazawa University Hospital between 2004 and 2015 were enrolled. We examined the morphology of the DPA using preoperative computed tomography and cancer progression along the DPA using resected specimens. We investigated the anatomical structures surrounding the DPA through cadaveric examination.

Results

The analysis of computed tomography images revealed the presence of the DPA in 141 patients. In typical cases, the DPA divides into a head and a body branch. Histopathological examination revealed cancer progression along the DPA in 32 patients. Cancer progression along the DPA was identified as a factor associated with a poor prognosis in pancreatic head or body cancer. Cadaveric examination showed the presence of abundant nerve and lymphatic tissues along the DPA.

Conclusions

It is important to remove the soft tissue surrounding the DPA during surgery for pancreatic head or body cancer because it may serve as an important route for cancer progression.
Important Radiologic and Clinical Factors for Predicting Overall Survival in Pancreatic Adenocarcinoma Patients Who Underwent FOLFIRINOX
Authors: Park Sae-Jin , Kim Jung Hoon , Choi Seo-Youn , Joo Ijin
Published: March 2024

Background

To predict poor overall survival (OS) in pancreatic adenocarcinoma (PAC) who underwent FOLFIRINOX (5-fluorouracil/leucovorin/irinotecan/oxaliplatin) using clinical and computed tomography (CT) findings.

Methods

A total of 189 patients with PAC who received FOLFIRINOX were retrospectively included. Two reviewers assessed CT findings and resectability based on National Comprehensive Cancer Network guidelines. They determined tumor size changes according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Delta measurements were performed. Clinical results, such as whether to perform surgery, were also investigated. A Cox proportional hazard model was used to identify significant predictors for OS. A CT-based nomogram was constructed to predict OS.

Results

Seventy-four patients (39.2%) underwent surgery. For OS, rim enhancement of PAC on baseline CT (hazard ratio [HR], 1.75; 95% confidence interval [CI], 1.10–2.77; P = 0.018), high delta tumor on baseline CT (HR, 2.46; 95% CI, 1.55–3.91; P < 0.001), progressive disease at follow-up CT (HR, 8.89; 95% CI, 2.94–26.87; P < 0.001), and without surgery (HR, 2.81; 95% CI, 1.49–5.30; P = 0.001) were important features related to poor prognosis. The nomogram showed good predictive ability for the survival.

Conclusion

Both clinical and CT findings were useful for predicting OS after FOLFIRINOX in PAC.
Second Recurrence of a Mitotically Active Cellular Fibroma From the Ovary
Authors: Wilkerson Casey , Barr Emma , Shahmohamady Babac , Abidi Alireza
Published: March 2024

BACKGROUND:

Mitotically active cellular fibroma is a benign fibromatous tumor of the ovary. It has 4 or more mitoses/10 high-power fields like a malignant sarcoma but has low-grade nuclear characteristics. Treatment is surgical excision, and recurrence is rare.

CASE:

We present a primary and secondary recurrence of mitotically active cellular fibroma. This patient was a 65-year-old woman who underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy for a large mitotically active cellular fibroma. She then had recurrences of the tumor 5 and 10 years later, requiring repeat resections.

CONCLUSION:

We recommend continued follow-up with these patients given the possibility for delayed recurrence and because follow-up and preventative treatment for these tumors are not well studied.
Prevalence of Bacterial Codetection and Outcomes for Infants Intubated for Respiratory Infections*
Authors: Karsies Todd , Shein Steven L. , Diaz Franco , Vasquez-Hoyos Pablo , Alexander Robin , Pon Steven , González-Dambrauskas Sebastián ,   with the Bronchiolitis And COdetectioN (BACON) Study Investigators; for the Bronchiolitis Subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators Network and the Red Colaborativa Pediátrica de Latinoamérica Network
Published: March 2024

OBJECTIVES:

To determine the prevalence of respiratory bacterial codetection in children younger than 2 years intubated for acute lower respiratory tract infection (LRTI), primarily viral bronchiolitis, and identify the association of codetection with mechanical ventilation duration.

DESIGN:

Prospective observational study evaluating the prevalence of bacterial codetection (moderate/heavy growth of pathogenic bacterial plus moderate/many polymorphonuclear neutrophils) and the impact of codetection on invasive mechanical ventilation (IMV) duration.

SETTING:

PICUs in 12 high and low/middle-income countries.

PATIENTS:

Children younger than 2 years old requiring intubation and ICU admission for LRTI and who had a lower respiratory tract culture obtained at the time of intubation between December 1, 2019, and November 30, 2020.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Of the 472 analyzed patients (median age 4.5 mo), 55% had a positive respiratory culture and 29% (n = 138) had codetection. 90% received early antibiotics starting at a median of 0.36 hours after respiratory culture. Median (interquartile range) IMV duration was 151 hours (88, 226), and there were 28 deaths (5.3%). Codetection was more common with younger age, a positive respiratory syncytial virus test, and an admission diagnosis of bronchiolitis; it was less common with an admission diagnosis of pneumonia, with admission to a low-/middle-income site, and in those receiving vasopressors. When adjusted for confounders, codetection was not associated with longer IMV duration (adjusted relative risk 0.854 [95% CI 0.684–1.065]). We could not exclude the possibility that codetection might be associated with a 30-hour shorter IMV duration compared with no codetection, although the CI includes the null value.

CONCLUSIONS:

Bacterial codetection was present in almost a third of children younger than 2 years requiring intubation and ICU admission for LRTI, but this was not associated with prolonged IMV. Further large studies are needed to evaluate if codetection is associated with shorter IMV duration.
Bacterial cholesterol-dependent cytolysins and their interaction with the human immune response
Authors: Sanford Tristan C. , Tweten Rodney K. , Abrahamsen Hunter L.
Published: March 2024

Purpose of review

Many cholesterol-dependent cytolysin (CDC)-producing pathogens pose a significant threat to human health. Herein, we review the pore-dependent and -independent properties CDCs possess to assist pathogens in evading the host immune response.

Recent findings

Within the last 5 years, exciting new research suggests CDCs can act to inhibit important immune functions, disrupt critical cell signaling pathways, and have tissue-specific effects. Additionally, recent studies have identified a key region of CDCs that generates robust immunity, providing resources for the development of CDC-based vaccines.

This review provides new information on how CDCs alter host immune responses to aid bacteria in pathogenesis. These studies can assist in the design of more efficient vaccines and therapeutics against CDCs that will enhance the immune response to CDC-producing pathogens while mitigating the dampening effects CDCs have on the host immune response.
Infectious mononucleosis: new concepts in clinical presentation, epidemiology, and host response
Authors: Naughton Patrick , Enright Frances , Lucey Brigid
Published: March 2024

Purpose of review

Infectious mononucleosis (IM) is an infectious disease that presents clinically in only a small percentage of individuals despite almost universal infection with the causative agent. Here, we review the latest concepts in the clinical presentation, epidemiology, and host response of this disease.

Recent findings

Several recently published papers/reviews describe IM as a condition caused by one of several etiologic agents including, cytomegalovirus (HHV-5), Roseola virus (HHV-6) and Toxoplasmosis amongst others; this review focuses on IM as solely caused by the human herpes virus 4 (HHV-4). Since the initial discovery of the virus in the 1960s and its subsequent discovery as the primary etiologic agent for IM it has been associated with several human cancers and autoimmune disorders. Recent published findings show a correlation between HHV-4 and the autoimmune disorder, multiple sclerosis (MS), suggesting earlier IM could possibly act as a causative factor. Considering the important links being made with IM to so many cancers and autoimmune disorders it is surprising that a standard investigative procedure has yet to be determined for this disease. A standard approach to the investigation of IM would ensure more cases are diagnosed, particularly atypical cases, this would benefit epidemiological studies, and more immediately help practitioners distinguish viral from bacterial throat infections, enabling them to treat accordingly.

The understanding of the latest concepts in clinical presentation, epidemiology and host response to IM would benefit greatly from the introduction of a standard procedure for its investigation and diagnosis.
HIV envelope trimers and gp120 as immunogens to induce broadly neutralizing antibodies in cows
Authors: Altman Pilar X. , Parren Mara , Sang Huldah , Ozorowski Gabriel , Lee Wen-Hsin , Smider Vaughn V. , Wilson Ian A. , Ward Andrew B. , Mwangi Waithaka , Burton Dennis R. , Sok Devin
Published: March 2024

The study of immunogens capable of eliciting broadly neutralizing antibodies (bnAbs) is crucial for the development of an HIV vaccine. To date, only cows, making use of their ultralong CDRH3 loops, have reliably elicited bnAbs following immunization with HIV Envelope trimers. Antibody responses to the CD4 binding site have been readily elicited by immunization of cows with a stabilized Env trimer of the BG505 strain and, with more difficulty, to the V2-apex region of Env with a cocktail of trimers. Here, we sought to determine whether the BG505 Env trimer could be engineered to generate new bnAb specificities in cows. Since the cow CD4 binding site bnAbs bind to monomeric BG505 gp120, we also sought to determine whether gp120 immunization alone might be sufficient to induce bnAbs. We found that engineering the CD4 binding site by mutation of a key binding residue of BG505 HIV Env resulted in a reduced bnAb response that took more immunizations to develop. Monoclonal antibodies isolated from one animal were directed to the V2-apex, suggesting a re-focusing of the bnAb response. Immunization with monomeric BG505 g120 generated no serum bnAb responses, indicating that the ultralong CDRH3 bnAbs are only elicited in the context of the trimer in the absence of many other less restrictive epitopes presented on monomeric gp120. The results support the notion of a hierarchy of epitopes on HIV Env and suggest that, even with the presence in the cow repertoire of ultralong CDRH3s, bnAb epitopes are relatively disfavored.
Habitat fragmentation enhances microbial collective defence
Authors: Verdon Nia , Popescu Ofelia , Titmuss Simon , Allen Rosalind J.
Published: March 2024

Microbes often inhabit complex, spatially partitioned geometries such as host tissue or soil, but the effects of habitat fragmentation on microbial infection dynamics and ecology are poorly understood. Here we investigate how habitat fragmentation impacts a prevalent microbial collective defence mechanism: enzymatic degradation of an environmental toxin. Using a theoretical model, we predict that habitat fragmentation can strongly enhance the collective benefits of enzymatic toxin degradation. For the clinically relevant case whereβ-lactamase producing bacteria mount a collective defence by degrading aβ-lactam antibiotic, we find that realistic levels of habitat fragmentation can allow a population to survive antibiotic doses that would far exceed those required to kill a non-fragmented population. This “habitat-fragmentation rescue” is a stochastic effect that originates from variation in bacterial density among different subpopulations and demographic noise. In contrast, the stochastic effects of habitat fragmentation are weaker in a model of collective enzymatic nutrient foraging. Our model suggests that treatment of a spatially complex, fragmented infection showing collective resistance may be far less effective than expected based on bulk population assumptions. This may help to explain lack of correlation between lab-measured antibiotic susceptibility values and clinical treatment success.
Unlocking the Genetic Potential ofSolanum bulbocastanum(SB22, Selection 22): A Valuable Resource for Enhancing Disease Resistance in Commercial Potato Cultivars
Authors: Shanmugavel Senthilkumar , Vinning Kelly , Talbot Sam C. , Brown Charles R. , Sathuvalli Vidyasagar
Published: March 2024

Cultivated potatoes are susceptible to a host of diseases caused by various pathogens. Wild relatives of potatoes are used in breeding programs as sources of resistance introgressed into cultivated potatoes. The wild potatoSolanum bulbocastanumis an essential source of resistance to Columbia root knot nematode (CRKN) and late blight. We present the initial chromosome-level assembly of SB22, produced using PacBio long reads and Dovetail Hi-C scaffolding. The final assembly size was 655.3 Mb. Using the BRAKER pipeline, 43,280 gene models were predicted, with a BUSCO completeness of about 90.3%. Repeat elements represented 63.8% of the genome, with LTR elements being the most abundant. DRAGO3 predicted 2,310 disease resistance-like genes across the 12 chromosomes of SB22; the MEME suite was used to identify their amino acid motifs. Putative candidate genes contributing to CRKN resistance were mapped on chromosome 11 of SB22. The SB22 draft genome is a valuable genomic resource for potato breeding programs.
FIS103, a Novel SULT1A1-dependent Prodrug, Demonstrates Potent Antitumor Activity in Renal Cell Carcinoma
Authors: Hamilton Ross A. , Saini Uksha , Tran Mai , Foley Christopher J. , Enagala Pooja , Chibas Leniher C. , Chatterjee Disha , Vega Stephanie P. , Chatterjee Dev , Varadhachary Atul
Published: March 2024

Intra-tumoral heterogeneity has been shaping the field of precision medicine for cancer patients ever since its emergence. Prodrugs, which require activation by tumor associated enzymes (TAEs), are a rapidly emerging approach for targeted therapeutics. SULT1A1, a sulfotransferase enzyme and TAE, is over-expressed in about 5-15% of cancer patients including breast, prostate and renal cell carcinoma (RCC); however, it is either not expressed or expressed at low level in most normal tissue. Bioinformatic RNA analyses revealed that SULT1A1 over-expression in tumors is correlated with worse patient prognosis. We have identified a new compound, FIS103, which is a small molecule anti-cancer prodrug that is activated by SULT1A1 once internalized. This class of compounds, N-benzyl indole carbinols (N-BICs), cause rapid cell death by inducing widespread non-specific covalent alkylation of proteins in the cancer cell. We report that FIS103 displays potent antitumor activity in SULT1A1 over-expressing RCC cell lines (A498 and Caki-1). Contrarily, low SULT1A1 expressing RCC cells (786-O and ACHN) did not show any antitumor effects, which suggests low FIS103 toxicity in the absence of SULT1A1.In silicomodeling validated the predicted SULT1A1-FIS103 interaction. Furthermore, FIS103 demonstrates potent SULT1A1-dependent antitumor activity in NU/J mouse xenografts injected with A498 cells. Remarkably, the flank tumors in mice regressed to non-measurable 14 days post-FIS103 treatment and did not regrow through the study conclusion. Additionally, SD rats treated with FIS103 once daily for 14 days demonstrated a promising liver toxicity profile with serum liver enzymes falling within the normal range and histopathology analysis indicated no difference between FIS103 or vehicle treated rats. We hereby demonstrate that FIS103 may have the potential to improve survival as well as quality of life of RCC patients and its application could be extended to other SULT1A1 expressing cancers.
Proteomics analysis of peripheral blood monocytes from patients in early dengue infection reveals potential markers of subsequent fluid leakage
Authors: Perera Nilanka , Kumar Abhinav , Gangadharan Bevin , Ranasinghe Diyanath , Wijewickrama Ananda , Malavige Gathsaurie Neelika , Miller Joanna L. , Zitzmann Nicole
Published: March 2024

Infections caused by dengue virus (DENV) cause significant morbidity and mortality worldwide. The majority of patients have a mild course of dengue fever (DF) disease, however a proportion of infected individuals develop much more severe dengue haemorrhagic fever (DHF) resulting in circulatory collapse and multiorgan failure due to increased vascular permeability. Early detection of individuals likely to develop severe disease could lead to improved outcomes for patients, and help use healthcare resources more efficiently. At present there are no reliable markers during the earlier stages of infection that indicate which patients will go on to develop DHF. Our study was aimed at identifying proteins that are differentially regulated early during disease in peripheral blood monocytes (PBMC) of patients who subsequently develop DHF. Such proteins may also point at cellular pathways implicated in developing vascular leakage. PBMC were isolated from patients with a confirmed dengue infection, lysed and subjected to tandem mass tag mass spectrometry. One hundred and sixty proteins were differentially expressed in DENV-infected samples compared to healthy controls. These were mainly involved in type I interferon signaling, cytokine response, phagocytosis, haemostasis and cell adhesion. PBMC from DHF patients differentially expressed 90 proteins compared to individuals with DF; these were involved in down-regulation of platelet activation and aggregation, cell adhesion and cytoskeleton arrangement pathways. Proteins involved in oxidative stress and p38 MAPK signaling were upregulated in DHF samples during early infection compared to DF samples. The proteins reported here that are differentially regulated in PBMC early during infection could potentially serve as biomarkers to identify patients at risk of developing DHF at an early disease stage. This study also provides important observations on pathways implicated in severe DENV infection.
The impact of positive surgical margin parameters and pathological stage on biochemical recurrence after radical prostatectomy: a systematic review and meta-analysis
Authors: Guo Hong , Zhang Lei , Shao Yuan , An Kunyang , Hu Caoyang , Liang Xuezhi , Wang Dongwen
Published: March 2024

Background

To systematically review and perform a meta-analysis on the predictive value of the primary Gleason grade (PGG) at the positive surgical margin (PSM), length of PSM, number of PSMs, and pathological stage of the primary tumor on biochemical recurrence (BCR) in patients with prostate cancer (PCa) after radical prostatectomy (RP).

Methods

A systematic literature search was performed using electronic databases, including PubMed, EMBASE, Cochrane Library, and Web of Science, from January 1, 2005, to October 1, 2023. The protocol was pre-registered in PROSPERO. Subgroup analyses were performed according to the different treatments and study outcomes. Pooled hazard ratios with 95% confidence intervals were extracted from multivariate analyses, and a fixed or random effect model was used to pool the estimates. Subgroup analyses were performed to explore the reasons for the heterogeneity.

Results

Thirty studies that included 46,572 patients with PCa were eligible for this meta-analysis. The results showed that, compared to PGG3, PGG4/5 was associated with a significantly increased risk of BCR. Compared with PSM ≤3 mm, PSM ≥3 mm was associated with a significantly increased risk of BCR. Compared with unifocal PSM, multifocal PSM (mF-PSM) was associated with a significantly increased risk of BCR. In addition, pT >2 was associated with a significantly increased risk of BCR compared to pT2. Notably, the findings were found to be reliable based on the sensitivity and subgroup analyses.

Conclusions

PGG at the PSM, length of PSM, number of PSMs, and pathological stage of the primary tumor in patients with PCa were found to be associated with a significantly increased risk of BCR. Thus, patients with these factors should be treated differently in terms of receiving adjunct treatment and more frequent monitoring. Large-scale, well-designed prospective studies with longer follow-up periods are needed to validate the efficacy of these risk factors and their effects on patient responses to adjuvant and salvage therapies and other oncological outcomes.
A Phase 1 Study of Novel Antiplatelet Agent to Overcome Pharmacogenomic Limitations of Clopidogrel
Authors: Pareek Anil , Chandurkar Nitin , Raut Vivek , Naidu Kumar
Published: March 2024

Background

Clopidogrel is the most commonly prescribed thienopyridine as part of dual antiplatelet therapy for the treatment of cardiovascular diseases. However, Clopidogrel responsiveness shows variability based on CYP2C19 polymorphism. Therefore, we planned a study with an objective of evaluating safety, tolerability, pharmacodynamics and pharmacokinetics of a novel thienopyridine antiplatelet agent AT-10 in healthy Indian subjects in comparison with standard dosage regimen of Clopidogrel based on their CYP2C19 genotyping.

Methods

Two CYP2C19 genotype based groups were identified i.e., Poor Metabolizer and Extensive Metabolizers with 20 subjects in each group (N=40) for participating in a randomized, two period, cross-over study. Each study period lasted 6 days including administration of loading and maintenance doses of AT-10 (40mg/10mg) or Clopidogrel (300mg/75mg). The pharmacokinetics and pharmacodynamics were assessed on day 1 and day 6 at several time intervals.

Results

Overall result of pharmacodynamic parameters showed that, mean % Inhibition of Platelet Aggregation between AT-10 and Clopidogrel in all subjects at Post-dose 6hr (loading dose) (AT-10: Clopidogrel; 73.30% vs. 18.53%) and Post-dose 6 hr on Day 6 (maintenance dose) (AT-10: Clopidogrel; 83.41% vs. 51.19 %) obtained from the AT-10 group was significantly higher than the Clopidogrel group. Further, %inhibition of platelet aggregation from AT-10 treatment in poor metabolizer group was significantly higher than the Clopidogrel treatments in extensive metabolizer group.

Overall pharmacokinetic comparison in all subjects indicates that AT-10 gives greater exposure to active Metabolite MP-H4 than Clopidogrel.

Conclusion

AT-10 may emerge as a promising anti-platelet drug and can be further developed in clinical studies for the unmet medical needs of cardiovascular diseases. CTRI Registration: CTRI/2021/03/032206

Clinical Perspectives

AT-10 (2-oxo-Clopidogrel) is a novel thienopyridine P2Y12 inhibitor under clinical development in India.

It is a Clopidogrel derivative that is metabolically converted to produce the active thiol metabolite similar to Clopidogrel.

The response to AT-10 was found unaffected by genetic CYP2C19 polymorphisms to the extent of its influence in Clopidogrel, thus eliminating the need for characterization of Clopidogrel responsiveness and thereby maintaining effectiveness in all patients, including those patients who are identified as CYP2C19 poor and intermediate metabolizers.

Further studies are required to investigate the influence of CYP2C19 functional polymorphisms on the response to AT-10 dose in diverse clinical settings, and especially on the risk of recurrent thrombotic events during AT-10 treatment as compared to Clopidogrel therapy.