bluuebunny/crossref_metadata_2025 huggingface dataset:
Beyond mortality: definitions and benchmarks of outcome standards in paediatric anaesthesiology
Authors: Olbrecht Vanessa A. , Engelhardt Thomas , Tobias Joseph D.
Published: February 2023

Purpose of review

The aim of this study was to review the evolution of safety and outcomes in paediatric anaesthesia, identify gaps in quality and how these gaps may influence outcomes, and to propose a plan to address these challenges through the creation of universal outcome standards and a paediatric anaesthesia designation programme.

Recent findings

Tremendous advancements in the quality and safety of paediatric anaesthesia care have occurred since the 1950 s, resulting in a near absence of documented mortality in children undergoing general anaesthesia. However, the majority of data we have on paediatric anaesthesia outcomes come from specialized academic institutions, whereas most children are being anaesthetized outside of free-standing children's hospitals.

Although the literature supports dramatic improvements in patient safety during anaesthesia, there are still gaps, particularly in where a child receives anaesthesia care and in quality outcomes beyond mortality. Our goal is to increase equity in care, create standardized outcome measures in paediatric anaesthesia and build a verification system to ensure that these targets are accomplished. The time has come to benchmark paediatric anaesthesia care and increase quality received by all children with universal measures that go beyond simply mortality.
Clinical Presentations and Treatment of Phenibut Toxicity and Withdrawal: A Systematic Literature Review
Authors: Weleff Jeremy , Kovacevich Alexsandra , Burson Jesse , Nero Neil , Anand Akhil
Published: February 2023

Objectives

This systematic review aimed to identify published articles that evaluated all phenibut toxicity and withdrawal cases to understand better their clinical presentations and treatments.

Methods

A comprehensive literature search was conducted using Medline (Ovid), Embase (Ovid), and Cochrane Library databases to capture all published cases on the presentations and management of phenibut toxicity or withdrawal.

Results

Sixty-two cases from 36 studies on presentation and management of phenibut toxicity or phenibut withdrawal were identified. Of all subjects, 80.7% were male. The average age was 30.9 years (SD, 13.2 years; range, 0–71 years). A total of 86.8% reported obtaining phenibut online, and 63.2% reported concomitant substance use with other addictive agents; benzodiazepines and alcohol were the most combined drugs. The average length of hospital stay was 5.0 days (n = 25; SD, 5.4 days; range, 1–25 days) for phenibut toxicity and 7.7 days (n = 20; SD, 7.8 days; range, 0–30 days) for phenibut withdrawals. The most common symptoms reported during phenibut toxicity were altered mental status, somnolence, psychosis, and movement disorders. Of the phenibut toxicity cases, 48.7% required intubation. Benzodiazepines and antipsychotics were most used to treat phenibut toxicity. For phenibut withdrawal cases, 95.7% reported daily use. The most common symptoms reported during phenibut withdrawals were anxiety, irritability or agitation, insomnia, and psychosis. Sixteen (69.6%) of phenibut withdrawal cases required multiple medications for treatment. Benzodiazepines, baclofen, atypical antipsychotics, gabapentanoids, and barbiturates were commonly used to treat phenibut withdrawals.

Conclusions

The seriousness of presentations, combined with the assortments of medications used for both syndromes, reflects the potential dangers of phenibut use and the need for systematized treatment protocols.
Human Atypical Monkeypox: Early Warning for Global Outbreak?
Authors: Wang Hui-Fang , Zhang Yang , Zhang Ji-Yuan , Wang Fu-Sheng
Published: February 2023

Monkeypox is usually considered as a zoonosis caused by monkeypox virus with potential threat to public health in the post–smallpox era. The recent outbreak of monkeypox began in May 7, 2022, and has been found in many countries out of Africa. The World Health Organization declared that this endemic is an “atypical” phenomenon with definite human-to-human transmission. To understand the situation more clearly, this review briefly summarizes the epidemiologic and clinical characteristics of the disease and highlights the clinical management and preventive strategies.
Glucose Metabolism and Human Immunodeficiency Virus Type 1 Infection
Authors: Chen Zhonghe , Wang Tiantian , Deng Kai
Published: February 2023

Acquired immune deficiency syndrome is still one of the most severe global infectious diseases that pose a significant threat to human health. With the successful application of antiretroviral therapy, productive replication of human immunodeficiency virus type 1 (HIV-1) can be effectively blocked; however, antiretroviral therapy alone cannot cure the infection because of the presence of a stable and reactivatable viral latent reservoir. Thus, it is of great importance to have a better comprehension of the mechanisms driving HIV-1 pathogenesis and long-term persistence in infected individuals, based on which to further discover novel targets for therapeutic applications to treat or even cure the infection. Various studies have revealed that cellular metabolism is a critical factor impacting the fate and intracellular activities of immune cells. Emerging evidence implies that the alternations of cellular metabolism induced by HIV-1 infection play an important role in HIV-1 pathogenesis. Consequently, a promising approach of “metabolism as a therapeutic target” raised the possibility of using metabolic reprogramming as a treatment option for chronic HIV-1 infection. In this review, we summarize the latest studies about the interplay of the hosts' reprogramming of glucose metabolism and HIV-1 infection and introduce potential applications of searching for hallmarks and therapeutic targets of metabolic interventions for HIV-1 infection.
Lipid-Based Poly(I:C) Adjuvants Strongly Enhance the Immunogenicity of SARS-CoV-2 Receptor-Binding Domain Vaccine
Authors: Wu Yixin , Meng Liuxian , Zhang Huicong , Hu Shun , Li Fusheng , Yu Yingjie
Published: February 2023

Background

The outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has greatly threatened public health. Recent studies have revealed that the spike receptor-binding domain (RBD) of SARS-CoV-2 is a potent target for vaccine development. However, adjuvants are usually required to strengthen the immunogenicity of recombinant antigens. Different types of adjuvants can elicit different immune responses.

Methods

We developed an RBD recombinant protein vaccine with a polyriboinosinic acid–polyribocytidylic acid [poly(I:C)] adjuvant to evoke a strong immune response. The delivery of poly(I:C) was optimized in two steps. First, poly(I:C) was complexed with a cationic polymer, poly-l-lysine (PLL), to form poly(I:C)–PLL, a polyplex core. Thereafter, it was loaded into five different lipid shells (group II, III-1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC], III-1,2-dioleoyl-sn-glycero-3-phosphoethanolamine [DOPE], IV-DOPE, and IV-DSPC). We performed an enzyme-linked immunosorbent assay and enzyme-linked immunosorbent spot assay to compare the ability of the five lipopolyplex adjuvants to enhance the immunogenicity of the SARS-CoV-2 RBD protein, including humoral and cellular immune responses. Finally, the adjuvant with the highest immunogenicity was selected to verify the protective immunity of the vaccine through animal challenge experiments.

Results

Recombinant RBD protein has low immunogenicity. The different adjuvants we developed enhanced the immunogenicity of the RBD protein in different ways. Among the lipopolyplexes, those containing DOPE (III-DOPE and IV-DOPE) elicited RBD-specific immunoglobulin G antibody responses, and adjuvants with four components elicited better RBD-specific immunoglobulin G antibody responses than those containing three components (P < 0.05). The IC50 and IC90 titers indicated that the IV-DOPE lipopolyplex had the greatest neutralization ability, with IC50 titers of 1/117,490. Furthermore, in the challenge study, IV-DOPE lipopolyplex protected mice from SARS-CoV-2 infection. On the fourth day after infection, the average animal body weights were reduced by 18.56% (24.164 ± 0.665 g vs. 19.678 ± 0.455 g) and 0.06% (24.249 ± 0.683 g vs. 24.235 ± 0.681 g) in the MOCK and vaccine groups, respectively. In addition, the relative expression of viral RNA in the vaccinated group was significantly lower than that in the MOCK group (P < 0.05). Interstitial inflammatory cell infiltration was observed in the MOCK group, whereas no obvious damage was observed in the vaccinated group.

Conclusions

The IV-DOPE–adjuvanted SARS-CoV-2 recombinant RBD protein vaccine efficiently protected mice from SARS-CoV-2 in the animal challenge study. Therefore, IV-DOPE is considered an exceptional adjuvant for SARS-CoV-2 recombinant RBD protein-based vaccines and has the potential to be further developed into a SARS-CoV-2 recombinant RBD protein-based vaccine.
Relative efficacy of intracameral moxifloxacin injection methods
Authors: Arshinoff Steve A. , Shi Runjie B.
Published: February 2023

Purpose:

To determine the amount of moxifloxacin remaining in the anterior chamber (AC), immediately after its injection using 3 current injection methods, assuming mixing and fluid exchange with the AC contents during injection of the drug, and to determine the most desirable injection method.

Setting:

Department of Ophthalmology and Vision Sciences and Institute of Biomedical Engineering, University of Toronto, Toronto, Canada.

Design:

Mathematical modeling.

Methods:

Mathematical modeling using first-order mixing methods were used to assess mixing.

Results:

The Kaiser method of injecting 0.5 mL × 100 μg/0.1 mL does not achieve the desired 500 μg level of moxifloxacin in the AC. The “straight from the bottle” method of injecting 0.1 mL × 500 μg/0.1 mL is fraught with potential error, yielding a relatively unreliable final amount in the AC. Injecting 0.5 to 0.6 mL × 150 μg/0.1 mL yields a result closest to the desired goal.

Conclusions:

Based on the calculation, the most accurate of current methods to deliver 500 μg moxifloxacin intracamerally is the method of 150 μg/0.1 mL × 0.5 to 0.6 mL.
Comparison of blood levels of vitamin B12, folic acid, riboflavin, and homocysteine in keratoconus and healthy subjects
Authors: Sozer Omer , Ozalp Onur , Atalay Eray , Demir Sukru Saygin , Alatas İbrahim Ozkan , Yildirim Nilgun
Published: February 2023

Purpose:

To evaluate blood levels of vitamin B12, folic acid, riboflavin, and homocysteine in keratoconus (KC) and healthy subjects.

Setting:

Eskişehir Osmangazi University, Eskişehir, Turkey.

Design:

Cross-sectional study.

Methods:

100 KC patients (patient group) between the ages of 18 to 35 years and 200 healthy individuals (control group) in the same age range were included in the Eskişehir Osmangazi University Hospital Eye Clinic between October 2019 and March 2020. In all cases, a complete ophthalmologic examination and corneal tomography evaluation with a Pentacam Scheimpflug camera were performed. In blood samples, vitamin B12 and folic acid levels were measured using an electrochemiluminescence immunoassay analyzer, and homocysteine and riboflavin levels were measured using high-performance liquid chromatography. Chi-square tests were used in the analysis of categorical variables, and Mann-Whitney U and Kruskal-Wallis tests were used in the analysis of numerical variables.

Results:

Homocysteine (13.0 ± 6.6 vs 12.1 ± 5.4 μmol/L, P = .190), vitamin B12 (313.5 ± 119.4 vs 322.9 ± 128.3 pg/mL, P = .619), and folic acid (7.0 ± 2.7 vs 7.4 ± 2.9 ng/mL, P = .230) levels were not different between KC (100 eyes of 100 subjects) and control (200 eyes of 200 subjects) groups. The mean riboflavin level was 84.0 ± 21.8 μg/L in the patient group and 183.6 ± 74.3 μg/L in the control group, with a significant difference between the 2 groups (P < .001). Riboflavin levels were below 180 μg/L in 99% (n = 99) of the cases in the KC group and 53.5% (n = 107) in the control group (P < .001).

Conclusions:

Low blood riboflavin levels in KC patients may be a possible risk factor in the pathogenesis of KC.
Follicular pancreatitis: Case report and literature review
Authors: Lee Wan-Sik , Kim Ki-Hyun , Noh Myung-Giun , Joo Young-Eun
Published: February 2023

Rationale:

Follicular pancreatitis is a very rare type of focal chronic pancreatitis and is often mistaken for pancreatic neoplasms. It is histologically characterized by extensive lymphoid follicular formation with reactive germinal centers.

Patient concerns:

A 50-year-old man was admitted to our hospital with 1-month history of epigastric pain. Contrast-enhanced computed tomography and magnetic resonance imaging revealed a 4.7 cm sized enhancing pancreatic head mass with anterior mesenteric soft tissue infiltration and superior mesenteric vein invasion. Endoscopic ultrasonography revealed an ill-defined hypoechoic mass in the head of the pancreas.

Diagnoses:

A laparoscopic surgical biopsy was performed. Hematoxylin-eosin staining showed the acini structure destruction within the pancreatic parenchyma and different-sized lymphoid follicles with reactive germinal centers around the duct. Immunohistochemical examination showed that cells were positive for the B-cell marker CD20, T-cell marker CD3, and slightly positive for IgG4. However, cells were negative for the B-cell marker Bcl-2. Follicular pancreatitis was confirmed based on the findings of histology and immunohistochemistry.

Interventions:

The patient was regularly followed without any specific treatment.

Outcomes:

Follow-up computed tomography revealed no change in the lesion 1 year after diagnosis.

Lessons:

To the best of our knowledge, this is the first case of follicular pancreatitis in Korea.
Postpartum Home Blood Pressure Monitoring Program
Authors: Hayden-Robinson Kamilah A. , Deeb Jessica L.
Published: February 2023

Background and Significance:

Hypertensive disorders of pregnancy complicate about 10% of pregnancies and are a leading cause of maternal morbidity and mortality.

Purpose:

The purpose of this quality improvement project was to evaluate a program to provide a home blood pressure monitor to all postpartum patients who had a hypertensive diagnosis and elevated blood pressure.

Methods:

The program includes a blood pressure monitor, instructions for its use, education about hypertension, and a guidance grid with standardized blood pressure parameters reviewed prior to discharge from the hospital. Patients are taught about potential adverse outcomes during postpartum. Patients are instructed to follow-up with their care provider based on the parameters. A retrospective medical record review was used to evaluate clinical outcomes.

Results:

Medical records of 185 patients indicated that 20% (n = 36) who received the home BP monitor reported one or more mild-to-severe range blood pressure(s) during postpartum. Twenty-eight percent (n = 52) had outpatient medication adjustments, including decreasing, increasing, starting, and discontinuing medications. Nine percent (n = 17) of patients returned to the obstetric triage for evaluation. There was patient overlap between those experiencing elevated blood pressures, medication adjustments, and those who returned to hospital for evaluation.

Clinical Implications:

Ongoing monitoring may improve identification and management of postpartum hypertension and potentially prevent progression to hypertensive-related adverse events.
Improving Cardiovascular Follow-Up after Diagnosis of a Hypertensive Disorder of Pregnancy using the Electronic Health Record
Authors: Burgess Adriane , Stover Samantha
Published: February 2023

Background:

Cardiovascular disease is the leading cause of death among women. Sex-specific risk factors for cardiovascular disease include history of a hypertensive disorder of pregnancy.

Problem:

After diagnosis of a hypertensive disorder of pregnancy, professional societies recommend follow-up with a primary care provider for preventative care. There are gaps in patient and health care provider knowledge of the association between a hypertensive disorder of pregnancy and cardiovascular disease. That gap has a negative effect on patients receiving recommended follow-up.

Methods:

An electronic registry was created to identify those who gave birth in our health system and had a diagnosis of hypertensive disorder of pregnancy. From this, information outreach was sent electronically to the patient and their primary care provider.

Interventions:

Communication in the outreach included education on the association between hypertensive disorders of pregnancy and cardiovascular disease, the importance of follow-up, cardiopreventative strategies, and biochemical assessment. Medical records were audited at approximately 6 months postpartum to determine if patients completed a visit with their primary care provider to discuss cardiovascular risks.

Results:

Between May 2021 and June 2022, 15% (n = 1,131) of patients who gave birth in our health system had a diagnosis of hypertensive disorder of pregnancy. Ninety percent of those patients who received outreach communication viewed the letter. At baseline, 16% of patients during postpartum with a hypertensive disorder of pregnancy saw their primary care provider to discuss cardiopreventative strategies. After implementation of our program, 26% of those with a hypertensive disorder of pregnancy saw their primary care provider for follow-up and discussed cardiopreventative strategies.

Clinical Implications:

Nurses should ensure that women during postpartum and their primary care providers are educated about the association of hypertensive disorders of pregnancy and long-term cardiovascular risk. The electronic health record may be an optimal way to ensure education is provided and follow-up scheduled.
Abdominal Imaging Findings on Computed Tomography as a Tool for COVID-19 Mortality Risk Assessment: Comparison With Chest Radiograph Severity Scores
Authors: Balthazar Patricia , Mercaldo Nathaniel , Pisuchpen Nisanard , Mendoza Dexter P. , Little Brent P. , Flores Efren J. , Kambadakone Avinash
Published: February 2023

Objective

To quantify the association between computed tomography abdomen and pelvis with contrast (CTAP) findings and chest radiograph (CXR) severity score, and the incremental effect of incorporating CTAP findings into predictive models of COVID-19 mortality.

Methods

This retrospective study was performed at a large quaternary care medical center. All adult patients who presented to our institution between March and June 2020 with the diagnosis of COVID-19 and had a CXR up to 48 hours before a CTAP were included. Primary outcomes were the severity of lung disease before CTAP and mortality within 14 and 30 days. Logistic regression models were constructed to quantify the association between CXR score and CTAP findings. Penalized logistic regression models and random forests were constructed to identify key predictors (demographics, CTAP findings, and CXR score) of mortality. The discriminatory performance of these models, with and without CTAP findings, was summarized using area under the characteristic (AUC) curves.

Results

One hundred ninety-five patients (median age, 63 years; 119 men) were included. The odds of having CTAP findings was 3.89 times greater when a CXR score was classified as severe compared with mild (P = 0.002). When CTAP findings were included in the feature set, the AUCs for 14-day mortality were 0.67 (penalized logistic regression) and 0.71 (random forests). Similar values for 30-day mortality were 0.76 and 0.75. When CTAP findings were omitted, all AUC values were attenuated.

Conclusions

The CTAP findings were associated with more severe CXR score and may serve as predictors of COVID-19 mortality.
Bodyweight-adjusted Contrast Media With Shortened Injection Duration for Step-and-Shoot Coronary Computed Tomography Angiography to Acquire Improved Image Quality
Authors: Jin Liang , Wang Kun , Wang Xiaodong , Li Cheng , Sun Yingli , Gao Pan , Xiao Yi , Li Ming
Published: February 2023

Purpose:

Shortened injection durations are not recommended in step-and-shoot coronary computed tomography angiography (CCTA). We aimed to evaluate the image quality of CCTA performed using bodyweight-adjusted iodinated contrast media (ICM) with different injection durations to generate an optimized ICM administration protocol to acquire convincible image quality in step-and-shoot CCTA.

Materials and Methods:

A total of 200 consecutive patients with suspected coronary artery disease (CAD) were enrolled in group A (N=50, 350 mgI/mL, bodyweight×0.8 mL/kg with a 13-s injection duration), group B (N=50, 350 mgI/mL, bodyweight×0.9 mL/kg with a 13-s injection duration), group C (N=50, 350 mgI/mL, bodyweight×0.8 mL/kg with a 12-s injection duration), and group D (N=50, 320 mgI/mL, bodyweight×0.8 mL/kg with a 13-s injection duration). Patient characteristics, ICM administration protocols, quantitative computed tomography (CT) value measurements, and qualitative image scores were analyzed and compared among the groups.

Results:

Groups A and D achieved the lowest ICM volume, saline volume, injection flow rate, and total iodine and iodine injection rates among the groups. All the CT values of the coronary arteries in all groups were >300 HU. All the observers’ average scores exceeded three points. In group A, the CT values showed significant positive correlation with the iodine injection rate (r=0.226, P<0.001), whereas the signal-to-noise ratio (r=−0.004, P=0.927) and contrast-to-noise ratio (r=−0.006, P=0.893) values were not.

Conclusions:

Bodyweight×0.8 mL/kg with a 13-second injection duration is a comprehensive option for step-and-shoot CCTA with improved image quality, and a 350 mgI/mL iodine concentration is preferred.
Exploration of Novel Genetic Evidence and Clinical Significance Into Hemifacial Microsomia Pathogenesis
Authors: Wang Xuetong , Chai Yuanhao , Zhang Yan , Chai Gang , Xu Haisong
Published: February 2023

The authors browsed through past genetic findings in hemifacial microsomia along with our previously identified mutations in ITGB4 and PDE4DIP from whole genome sequencing of hemifacial microsomia patients. Wondering whether these genes influence mandibular bone modeling by regulation on osteogenesis, the authors approached mechanisms of hemifacial microsomia through this investigation into gene knockdown effects in vitro. MC3T3E1 cells were divided into 5 groups: the negative control group without osteogenesis induction or siRNA, the positive control group with only osteogenesis induction, and 3 gene silenced groups with both osteogenesis induction and siRNA. Validation of transfection was through fluorescence microscopy and quantitative real-time Polymerase chain reaction on knockdown efficiency. Changes in expression levels of the 3 genes during osteogenesis and impact of Itgb4 and Pde4dip knockdown on osteogenesis were examined by quantitative real-time Polymerase chain reaction, alkaline phosphatase, and alizarin red staining. Elevation of osteogenic genes Alpl, Col1a1, Bglap, Spp1, and Runx2 verified successful osteogenesis. Both genes were upregulated under osteogenic induction, while they had different trends over time. Intracellular fluorophores under microscope validated successful transfection and si-m-Itgb4_003, si-m-Pde4dip_002 had satisfactory knockdown effects. During osteogenesis, Pde4dip knockdown enhanced Spp1 expression (1.95±0.13 folds, P=0.045). The authors speculated that these genes may have different involvements in osteogenesis. Stimulated expression of Spp1 by Pde4dip knockdown may suggest that Pde4dip inhibits osteogenesis.
Temperature modifies trait-mediated infection outcomes in aDaphnia–fungal parasite system
Authors: Sun Syuan-Jyun , Dziuba Marcin K. , Jaye Riley N. , Duffy Meghan A.
Published: February 2023

One major concern related to climate change is that elevated temperatures will drive increases in parasite outbreaks. Increasing temperature is known to alter host traits and host–parasite interactions, but we know relatively little about how these are connected mechanistically—that is, about how warmer temperatures impact the relationship between epidemiologically relevant host traits and infection outcomes. Here, we used a zooplankton–fungus (Daphnia dentifera–Metschnikowia bicuspidata) disease system to experimentally investigate how temperature impacted physical barriers to infection and cellular immune responses. We found thatDaphniareared at warmer temperatures had more robust physical barriers to infection but decreased cellular immune responses during the initial infection process. Infected hosts at warmer temperatures also suffered greater reductions in fecundity and lifespan. Furthermore, the relationship between a key trait—gut epithelium thickness, a physical barrier—and the likelihood of terminal infection reversed at warmer temperatures. Together, our results highlight the complex ways that temperatures can modulate host–parasite interactions and show that different defense components can have qualitatively different responses to warmer temperatures, highlighting the importance of considering key host traits when predicting disease dynamics in a warmer world.

This article is part of the theme issue ‘Infectious disease ecology and evolution in a changing world’.
Can pharmaceutical pollution alter the spread of infectious disease? A case study using fluoxetine
Authors: Aulsebrook Lucinda C. , Wong Bob B. M. , Hall Matthew D.
Published: February 2023

Human activity is changing global environments at an unprecedented rate, imposing new ecological and evolutionary ramifications on wildlife dynamics, including host–parasite interactions. Here we investigate how an emerging concern of modern human activity, pharmaceutical pollution, influences the spread of disease in a population, using the water flea
Daphnia magna
and the bacterial pathogen
Pasteuria ramosa
as a model system. We found that exposure to different concentrations of fluoxetine—a widely prescribed psychoactive drug and widespread contaminant of aquatic ecosystems—affected the severity of disease experienced by an individual in a non-monotonic manner. The direction and magnitude of any effect, however, varied with both the infection outcome measured and the genotype of the pathogen. By contrast, the characteristics of unexposed animals, and thus the growth and density of susceptible hosts, were robust to fluoxetine. Using our data to parameterize an epidemiological model, we show that fluoxetine is unlikely to lead to a net increase or decrease in the likelihood of an infectious disease outbreak, as measured by a pathogen's transmission rate or basic reproductive number. Instead, any given pathogen genotype may experience a twofold change in likely fitness, but often in opposing directions. Our study demonstrates that changes in pharmaceutical pollution give rise to complex genotype-by-environment interactions in its influence of disease dynamics, with repercussions on pathogen genetic diversity and evolution.

This article is part of the theme issue ‘Infectious disease ecology and evolution in a changing world’.
Infection burdens and virulence under heat stress: ecological and evolutionary considerations
Authors: Hector T. E. , Gehman A.-L. M. , King K. C.
Published: February 2023

As a result of global change, hosts and parasites (including pathogens) are experiencing shifts in their thermal environment. Despite the importance of heat stress tolerance for host population persistence, infection by parasites can impair a host's ability to cope with heat. Host–parasite eco-evolutionary dynamics will be affected if infection reduces host performance during heating. Theory predicts that within-host parasite burden (replication rate or number of infecting parasites per host), a key component of parasite fitness, should correlate positively with virulence—the harm caused to hosts during infection. Surprisingly, however, the relationship between within-host parasite burden and virulence during heating is often weak. Here, we describe the current evidence for the link between within-host parasite burden and host heat stress tolerance. We consider the biology of host–parasite systems that may explain the weak or absent link between these two important host and parasite traits during hot conditions. The processes that mediate the relationship between parasite burden and host fitness will be fundamental in ecological and evolutionary responses of host and parasites in a warming world.

This article is part of the theme issue ‘Infectious disease ecology and evolution in a changing world’.
Aristophania vespae gen. nov., sp. nov., isolated from wasps, is related to Bombella and Oecophyllibacter, isolated from bees and ants
Authors: Guzman Juan , Won Miyoung , Poehlein Anja , Sombolestani Atena Sadat , Mayorga-Ch Daniela , Laureys David , Clippeleer Jessika De , Kämpfer Peter , Daniel Rolf , Vilcinskas Andreas , Vandamme Peter , Kwon Soon-Wo
Published: February 2023

Acetic acid bacteria (family

Acetobacteraceae

) are found in the gut of most insects. Two clades are currently recognized: Commensalibacter–Entomobacter and

Bombell

a–

Oecophyllibacter

. The latter group is only found in hymenopteran insects and the described species have been isolated from bees and ants. In this study, two new strains DDB2-T1T (=KACC 21507T=LMG 31759T) and DM15PD (=CCM 9165=DSM 112731=KACC 22353=LMG 32454) were isolated from wasps collected in the Republic of Korea and Germany, respectively. Molecular and phenotypic analysis revealed that the strains are closely related, with 16S rRNA gene sequences showing 100 % identity and genomic average nucleotide identity (ANI) values ≥99 %. The closest related species based on type strain 16S rRNA gene sequences are

Swingsia samuiensis

,

Acetobacter peroxydans

,

Bombella favorum

and

Bombella intestini

(94.8–94.7% identity), whereas the closest related species based on type strain genome analysis are

Saccharibacter floricola

and

Bombella intestini

(ANI values of 68.8 and 68.2 %, respectively). The reconstruction of a phylogenomic tree based on 107 core proteins revealed that the branch leading to DDB2-T1T and DM15PD is localized between

Oecophyllibacter

and Saccharibacter–Bombella. Further genomic distance metrics such as ANI, percentage of conserved proteins and alignment fraction values were consistent with these strains belonging to a new genus. The key phenotypic characteristics were one MALDI-TOF-MS peak (m/z=4601.9±2.0) and the ability to produce acid from d-arabinose. Based on this polyphasic approach, including phylogenetics, phylogenomics, genome distance calculations, ecology and phenotypic characteristics, we propose to name the novel strains Aristophania vespae gen. nov., sp. nov., with the type strain DDB2-T1T (=KACC 21507T=LMG 31759T).
A prospective study on tumour response assessment methods after neoadjuvant endocrine therapy in early oestrogen receptor positive breast cancer
Authors: López-Velazco Joanna I. , Manzano Sara , Otaño María , Elorriaga Kepa , Bultó Núria , Herrero Julio , Lahuerta Ainhara , Segur Virginia , Álvarez-López Isabel , Caffarel Maria M. , Urruticoechea Ander
Published: February 2023

Neoadjuvant endocrine therapy (NET) in oestrogen receptor-positive/HER2-negative breast cancer (ER+/HER2-BC) allows real-time evaluation of drug efficacy and biological changes upon estrogenic deprivation. Clinical and pathological evaluation after NET may be used to obtain prognostic and predictive information of tumour response. Scales developed to evaluate response after neoadjuvant chemotherapy are not useful and there are not many validated biomarkers to assess response to NET. In this prospective study, we analysed radiological and pathological tumour response of 104 postmenopausal ER+/HER2-BC patients, treated with NET for a mean of 7 months. Our results show that radiological evaluation underestimates pathological tumour size, although it can be used to assess tumour response. In addition, we propose that the tumour cellularity size (TCS), calculated as the product of the residual tumour cellularity in the surgical specimen and the tumour pathological size, could become a new tool to standardize response assessment to NET. It is simple, reproducible and correlates with the existing biomarkers. Our findings shed light on the dynamics of NET response, challenge the paradigm of the ability of NET to decrease surgical volume and point to the utility of the TCS to quantify the scattered tumour response usually produced by endocrine therapy.
A Methylation-Phosphorylation Switch Controls EZH2 Stability and Hematopoiesis
Authors: Guo Pengfei , Rajawasam Keshari , Trinh Tiffany , Sun Hong , Zhang Hui
Published: February 2023

The Polycomb Repressive Complex 2 (PRC2) methylates H3K27 to regulate development and cell fate by transcriptional silencing. Alteration of PRC2 is associated with various cancers. Here, we show that mouseLsd1/Kdm1adeletion causes dramatic reduction of PRC2 proteins, whereas mouse null mutation ofL3mbtl3orDcaf5results in PRC2 accumulation and increased H3K27 trimethylation. The catalytic subunit of PRC2, EZH2, is mono-methylated at lysine 20 (K20), promoting EZH2 proteolysis by L3MBTL3 and the CLR4DCAF5ubiquitin ligase. LSD1 demethylates the methylated K20 to stabilize EZH2. K20 methylation is inhibited by AKT-mediated phosphorylation of serine 21 in EZH2. Mouse K20R mutants develop hepatosplenomegaly associated with high GFI1B expression, and K20R mutant bone marrows expand hematopoietic stem cells and downstream hematopoietic populations. Our studies reveal that EZH2 is regulated by methylation dependent proteolysis, which is negatively controlled by AKT-mediated S21 phosphorylation to establish a methylation-phosphorylation switch to control the PRC2 activity and hematopoiesis.
High-resolution lac insect genome assembly provides genetic insights into lac synthesis and evolution of scale insects
Authors: Wang Weiwei , Chen Xiaoming , Bashir Nawaz Haider , Lu Qin , Zhang Jinwen , Ling Xiaofei , Ding Weifeng , Chen Hang
Published: February 2023

Lac insect is an important resource insect with great commercial value. However, the lack of its genome information restricts the fundamental biological research and applied studies of this species. Here, we first assembled the contig ofKerria laccausing Illumina and Nanopore sequencing by Hi-C and T2T techniques to obtain the genome ofK. laccaat the chromosome 0 gap level. The genome ofK. laccawas 256.62 Mb and the Scaffold N50 was 28.53 Mb. A total of 56.94 Mb of repeat sequences, constituting 22.19% of the assembled genome, were identified. We annotated 10,696 protein-encoding geneswith 89.74% annotated. By horizontal gene transfer analysis, we obtained a putative gene Isoprenyl diphosphate synthase (IPPS), a key enzyme in the isoprene synthesis pathway in the regulation of lac biosynthesis that transferred horizontally from bacteria to the genome ofK. lacca. Meanwhile, we constructed the lac synthesis biosynthetic pathway and screened 25 putative key genes in the synthesis pathway by transcriptome analysis in different developmental stages and tissues. It provides new research ideas to reveal the molecular mechanism of lac biosynthesis and regulation. The high-quality chromosomal-level genome of lac insect will provide a basis for the study of development, genetics, and the evolution of scale insects.
Gene regulatory patterning codes in early cell fate specification of theC. elegansembryo
Authors: Cole Alison G. , Hashimshony Tamar , Du Zhuo , Yanai Itai
Published: February 2023

Pattern formation originates during embryogenesis by a series of symmetry-breaking steps throughout an expanding cell lineage. InDrosophila, classic work has shown that the embryo segmentation is established by morphogens within a syncytium, and the subsequent action of the gap, pair-rule, and segment polarity genes. This classic model however does not translate directly to species that lack a syncytium – such asC. elegans– where cell fate is specified by cell-autonomous cell lineage programs and their inter-signaling. Previous single-cell RNA-Seq studies inC. eleganshave analyzed cells from a mixed suspension of cells from many embryos to study late differentiation stages, or individual early stage embryos to study early gene expression in the embryo. To study the intermediate stages of early and late gastrulation (28- to 102- cells stages) missed by these approaches, here we determine the transcriptomes of the 1- to 102-cell stage to identify 119 embryonic cell-states during cell-fate specification, including ‘equivalence-group’ cell identities. We find that gene expression programs are modular according to the sub-cell lineages, each establishing a set of stripes by combinations of transcription factor gene expression across the anterior-posterior axis. In particular, expression of the homeodomain genes establishes a comprehensive lineage-specific positioning system throughout the embryo beginning at the 28-cell stage. Moreover, we find that genes that segment the entire embryo inDrosophilahave orthologs inC. elegansthat exhibit sub-lineage specific expression. These results suggest that theC. elegansembryo is patterned by a juxtaposition of distinct lineage-specific gene regulatory programs each with a unique encoding of cell location and fate. This use of homologous gene regulatory patterning codes suggests a deep homology of cell fate specification programs across diverse modes of development.
The Mexican Cavefish Mount a Rapid and Sustained Regenerative Response Following Skeletal Muscle Injury
Authors: Olsen Luke , Hassan Huzaifa , Keaton Sarah , Rohner Nicolas
Published: February 2023

Physical injury and tissue damage is prevalent throughout the animal kingdom, with the ability to quickly and efficiently regenerate providing a selective advantage. The skeletal muscle possesses a uniquely large regenerative capacity within most vertebrates, and has thus become an important model for investigating cellular processes underpinning tissue regeneration. Following damage, the skeletal muscle mounts a complex regenerative cascade centered around dedicated muscle stem cells termed satellite cells. In non-injured muscle, satellite cells remain in a quiescent state, expressing the canonical markerPax7(Chen et al. 2020). However, following injury, satellite cells exit quiescence, enter the cell cycle to initiate proliferation, asymmetrically divide, and in many cases terminally differentiate into myoblasts, ultimately fusing with surrounding myoblasts and pre-existing muscle fibers to resolve the regenerative process (Chen et al. 2020).
Nanoparticle-Functionalized Acrylic Bone Cement for Local Therapeutic Delivery to Spinal Metastases
Authors: Siddique Ateeque , Cooke Megan E. , Weber Michael H. , Rosenzweig Derek H.
Published: February 2023

Polymethylmethacrylate bone cement is often used to reconstruct critical-sized defects generated by surgical resection of spinal metastases. Residual tumor cells after a resection can drive recurrence and destabilization. Doxorubicin (DOX) is a common chemotherapeutic drug with unwanted side-effects when administered systemically. Mesoporous silica nanoparticles are gaining attention for targeted drug delivery to bypass the negative side effects associated with systemic drug administration. We developed a nanoparticle-functionalized cement for the local release of DOX and tested its ability to suppress cancer cells. DOX was loaded onto nanoparticles which were then mixed into the cement. Drug release profiles were obtained over a period of 4 weeks. Cement constructs were incubated with 2D and 3D cultures of breast and prostate cancer cell lines, and cell metabolic activity and viability were evaluated. Cell migration and spheroid growth were assessed in collagen-coated spheroid cultures. Nanoparticles were homogenously dispersed and did not alter cement mechanical strength. A sustained DOX release profile was achieved with the addition of nanoparticles to the bone cement. The release profile of DOX from nanoparticle cement may be modified by varying the amount of the drug loaded onto the nanoparticles and the proportion of nanoparticles in the cement. Cells treated with the cement constructs showed a dose- and time-dependent inhibition. Cell migration and spheroid growth were impaired in 3D culture. We show that nanoparticles are essential for sustained DOX release from bone cement. DOX-loaded nanoparticle cement can inhibit cancer cells and impair their migration, with strong potential forin vivotranslation studies.
Origin and Development of the Claustrum in Rhesus Macaque
Authors: Li Hong , Duque Alvaro , Rakic Pasko
Published: February 2023

Understanding the claustrum’s functions has recently progressed thanks to new anatomical and behavioral studies in rodents, which suggest that it plays an important role in attention, salience detection, slow-wave generation, and neocortical network synchronization. Nevertheless, knowledge about the origin and development of the claustrum, especially in primates, is still limited. Here, we show that neurons of rhesus macaque claustrum primordium are generated between embryonic day E48 and E55 and express some neocortical molecular markers, such as NR4A2, SATB2, and SOX5. However, in the early stages, it lacks TBR1 expression, which separates it from other surrounding telencephalic structures. We also found that two waves of neurogenesis (E48 and E55) in the claustrum, corresponding to the birthdates of layers 6 and 5 of the insular cortex, establish a “core” and “shell” cytoarchitecture, which is potentially a basis for differential circuit formation and could influence information processing underlying higher cognitive functions of the claustrum. In addition, parvalbumin-positive interneurons are the dominant interneuron type in the claustrum in fetal macaque, and their maturation is independent of that in the overlaying neocortex. Finally, our study reveals that the claustrum is likely not a continuance of subplate neurons of the insular cortex, but an independent pallial region, suggesting its potentially unique role in cognitive control.

Significance Statement

The claustrum is believed to have a role in many high cognitive functions. However, the origin and development of this mysterious structure remain unknown, and the understanding of its relationship with the neocortex is ambiguous. Here we examined neuron origin and development of claustrum in rhesus macaque during the prenatal and postnatal periods. We found that the claustrum is formed as an independent telencephalic area as early as E55, and it seems not related to the subplate of the insula, although it shares some molecular characteristics with the neocortex. The claustrum excitatory neurons are generated sequentially around E48 and E55 and build a “core and shell” structure that may be a basic computing neuronal circuit unit underlying higher cognitive functions.
p53 and RB Cooperate to Suppress Transposable Elements
Authors: Lopez Omar M. , Zhang Michelle , Hendrickson Peter G. , Huang Jianguo , Daniel Andrea R. , Blackmer Jane , Luo Lixia , Attardi Laura D. , Corcoran David , Kirsch David G.
Published: February 2023

Accumulating data suggest that the long interspersed nuclear element 1 (LINE1), a major class of transposable elements, can promote tumorigenesis by causing deletions of tumor suppressor genes, amplifications of oncogenes, and chromosomal translocations(1). LINE1 and other transposable elements such as short interspersed nuclear elements (SINEs) can be activated during cancer development. Aberrant transposon expression has been correlated with loss of p53, however, how the loss of p53 or other tumor suppressors leads to activation of transposons during tumorigenesis remains to be fully understood. Here, we investigate the link between loss of the p53 and RB tumor suppressors and derepression of transposable elements. We observe that loss of p53 and RB in mouse embryonic fibroblasts leads to epigenetic changes, such as loss of DNA and histone methylation, which correlate with marked upregulation of LINE and SINE transposable elements. These results suggest that p53 and RB may utilize epigenetic mechanisms that work in tandem to suppress transposons, which may contribute to tumor suppression.

Significance

The two most commonly mutated genes in human cancer arep53and the retinoblastoma (RB) tumor suppressors. Together, these genes regulate complex interconnecting pathways responsible for the regulation of cell growth, cell death, and genomic integrity. Studies in genetically engineered mouse models demonstrate that the canonical functions of these two tumor suppressors fail to fully explain their tumor suppressive capabilities. Individually, p53 and RB have each been implicated in repressing transposons. Here we show that combined loss of p53 and RB, which rapidly transforms cells, also results in cooperative upregulation of transposable elements and coincides with decreased methylation of DNA and H3K9. Our results present a framework by which p53 and RB work together to restrain the expression of LINE1 and SINEs, which may contribute to tumor suppression.
Paradoxical activation of oncogenic signaling as a cancer treatment strategy
Authors: Dias Matheus Henrique , Friskes Anoek , Wang Siying , Fernandes Neto Joao M. , van Gemert Frank , Mourragui Soufiane , Kuiken Hendrik J. , Mainardi Sara , Alvarez-Villanueva Daniel , Lieftink Cor , Morris Ben , Dekker Anna , van Dijk Emma , Papagianni Chrysa , da Silva Marcelo S. , Jansen Robin , Mulero-Sánchez Antonio , Malzer Elke , Vidal August , Santos Cristina , Salazar Ramón , Wailemann Rosangela A. M. , Torres Thompson E. P. , De Conti Giulia , Raaijmakers Jonne A. , Snaebjornsson Petur , Yuan Shengxian , Qin Wenxin , Kovach John S. , Armelin Hugo A. , Riele Hein te , van Oudenaarden Alexander , Jin Haojie , Beijersbergen Roderick L. , Villanueva Alberto , Medema Rene H. , Bernards Rene
Published: February 2023

Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress-response programs that counteract the inherent toxicity of such aberrant signaling. While inhibition of oncogenic signaling pathways has been explored extensively, there is increasing evidence that overactivation of the same pathways can also disrupt cancer homeostasis and cause lethality. We show here that inhibition of Protein Phosphatase 2A (PP2A) hyperactivates multiple oncogenic pathways and engages stress responses in colon cancer cells. Genetic and compound screens identify combined inhibition of PP2A and WEE1 as synergistic in multiple cancer models by collapsing DNA replication and triggering premature mitosis followed by cell death. This combination also suppressed the growth of patient-derived tumorsin vivo. Remarkably, acquired resistance to this drug combination suppressed the ability of colon cancer cells to form tumorsin vivo. Our data suggest that paradoxical activation of oncogenic signaling can result in tumor suppressive resistance.