bluuebunny/crossref_metadata_2025 huggingface dataset:
COVID-19 Stay at Home Restrictions and the Interpretation of Emergency Powers: A Comparative Analysis
Authors: Chen Bruce
Published: November 2022

The COVID-19 pandemic has created immense challenges for governments in their management of the public health response and tested the limits of public law. This article undertakes a comparative analysis of the common law jurisdictions of the United Kingdom, New Zealand, and Australia. It discusses the imposition of ‘stay at home’ restrictions pursuant to public health legislative frameworks, focusing on judicial scrutiny in the context of statutory interpretation. It examines the appellate cases of R (Dolan) v Secretary of State for Health and Social Care [2021] 1 WLR 2326, Borrowdale v Director-General of Health [2022] 2 NZLR 356, and Kassam v Hazzard (2021) 106 NSWLR 520.

Using these case studies, this article seeks to reveal key themes and implications for public law. What approaches have the courts adopted to construe public health emergency powers? How have the courts treated ‘rights-based’ principles of statutory interpretation? Have the courts approached interpretation in the usual manner or displayed an unorthodox level of deference to other branches of government? The article concludes on what implications the judicial approaches have for the interpretation of emergency powers in the future.
The Blueberry Fruit Mycobiome Varies by Tissue Type and Fungicide Treatment
Authors: Szymanski Shay , Longley Reid , Hatlen Ross Joaquin , Heger Lexi , Sharma Nancy , Bonito Gregory , Miles Timothy D.
Published: November 2022

The microbial ecology of agricultural products may provide crucial insights into the management of postharvest fruit rots. To investigate postharvest microbial communities of highbush blueberry ( Vaccinium corymbosum), five fungicide spray programs were evaluated for their influence on the mycobiome of fruit skin and within the fruit pulp. The mycobiome was characterized by sequencing amplicons of the internal transcribed spacer 1 (ITS1) region with primers ITS1f and ITS4 with the Illumina MiSeq 300bp v3 system. Two of the five programs utilized commercial biological fungicides, two utilized azoxystrobin, and one utilized a series of treatments to simulate a realistic disease management program. Fungicide applications reduced diversity of the fruit skin mycobiome ( R2 = 0.409, P = 0.0001) and had a moderate impact on the pulp mycobiome ( R2 = 0.233, P = 0.0001). The mycobiome of the fruit pulp was also more variable than the skin mycobiome. In comparison with the untreated controls, each fungicide treatment program had a strongly significant effect on the β diversity of the blueberry fruit skin mycobiome ( R2 = 0.53 to 0.73, P = 0.0001). In the pulp, three of the five treatments had moderate but significant effects on β diversity in comparison with the control ( R2 = 0.10 to 0.18, P = 0.0005 to 0.017). Most samples indicated that fungi belonging to genera Epicoccum, Papiliotrema, and Sporobolomyces were widely prevalent and abundant across treatments and tissues. Fruit pathogen Botrytis cinerea was particularly abundant in the pulp of three of the fungicide treatments. Results from this study provide a baseline for future exploration of postharvest rot pathology and provide a community context on how fungicides may alter fungal communities in agricultural systems.
An update on patient reported outcomes in type 2 inflammation airway disease
Authors: Pedersen Christian Korsgaard , Haase Christiane , Aanaes Kasper , von Buchwald Christian , Backer Vibeke
Published: November 2022

Purpose of review

Patient reported outcome measures (PROMs) play an important role in assessing so-called global airway disease caused by type-2 inflammation, not only in terms of patients’ perspective on symptoms and treatment/side-effect, but they can also serve as a measure of disease control, and not least as an indicator of possible coexisting comorbidity otherwise unrecognized. The objective of this review was to investigate any newly developed PROMs for global airway disease and to give an overview of the most commonly used PROMs in the management of global airway disease.

Recent findings

The Standard Tests for Asthma, Allergic Rhinitis and Rhinosinusitis (STARR-15) is a recently developed PROM aimed to raise clinicians’ awareness of coexisting type-2 inflammation disease. Strengths of the STARR-15 is that is quick and symptom-centered, i.e. items are not specifically aimed at a disease the patients might not be aware they have. The STARR-15 has, however, not yet been validated, so details of responsiveness and reproducibility are yet to be determined.

PROMs are a quick and cheap way to assess patient perspectives in global airway disease, and can play an important role in unveiling otherwise overlooked co-existing double disease.
Advances in osteoarthritis imaging
Authors: Chalian Majid , Roemer Frank W. , Guermazi Ali
Published: November 2022

Purpose of review

Imaging plays a pivotal role for diagnosis, follow-up and stratification of osteoarthritis patients in clinical trials and research. We aim to present an overview of currently available and emerging imaging techniques for osteoarthritis assessment and provide insight into relevant benefits and pitfalls of the different modalities.

Recent findings

Although radiography is considered sufficient for a structural diagnosis of osteoarthritis and is commonly used to define eligibility of patients for participation in clinical trials, it has inherent limitations based on the projectional nature of the technique and inherent challenges regarding reproducibility in longitudinal assessment. MRI has changed our understanding of the disease from ‘wear and tear’ of cartilage to a whole organ disorder. MRI assessment of structural changes of osteoarthritis includes semi-quantitative, quantitative and compositional evaluation. Ultrasound is helpful in evaluating the degree of synovitis and has value in the assessment particularly of the patella-femoral joint. Recent development of computed tomography technology including weight-bearing systems has led to broader application of this technology in a research context.

Advances in MRI technology have resulted in a significant improvement in understanding osteoarthritis as a multitissue disease
Application of Accepted Use Criteria for the Treatment of Developmental Dysplasia of the Hip Decreases the Number of Infants Treated With a Pavlik Harness
Authors: Murphy-Zane Margaret S. , Carry Patrick M. , Salton Reba L. , Hadley Miller Nancy , Holmes Kaley , Freeman Tyler , Belton Matthew , Kohuth Brian , Burke Deborah , Georgopoulos Gaia
Published: November 2022

Background:

This analysis examined how the application of the American Academy of Orthopedic Surgeons appropriate use criteria (AUC) for developmental dysplasia of the hip in infants would change treatment patterns and outcomes for Graf IIA hips at a single quaternary pediatric hospital.

Methods:

After Institutional Review Board approval, patient medical records were reviewed and data were collected. Graf IIa hips were defined as alpha angle (AA) 50 to 59 degrees. AA and femoral head coverage (FHC) were measured from initial and 6-month ultrasounds and acetabular index (AI) was measured from radiographs at 6 months of age. Instability (positive Ortolani and Barlow tests) was noted. On the basis of the American Academy of Orthopedic Surgeons AUC for managing developmental dysplasia of the hip, hips were further categorized as normal (FHC ≥45%), borderline (FHC 35% to 44%), or dysplastic (FHC <35%).

Results:

Overall, 13% (49/371) of Graf IIa hips (AA 50 to 59 degrees) were dysplastic (FHC <35%). Total 24% (89/371) were clinically unstable. Total 42% (37/89) of unstable Graf IIa hips were dysplastic. Only 4% of stable Graf IIa hips were dysplastic (12/282). Out of 371 Graf IIa hips, 256 were treated with Pavlik harness (n=250) or Rhino brace (n=6). Among stable, nondysplastic (SND) hips (those with normal and borderline FHC≥35%), 33% (52/158) were treated because of a more severe contralateral side. If the AUC had been applied, 67% (106/158) of SND Graf IIa hips would not have been treated. Among the n=162 hips that returned for a 6-month radiograph, there was no difference in AI in the 115 treated and 47 untreated SND hips (mean difference treatment vs. no treatment: −1.5, 95% CI, −3.1 to 0.2, P=0.0808).

Conclusions:

Using AUC recommendations, our center could reduce the number of SND Graf IIa hips we treat by 67%. Although 24% of Graf IIa hips were clinically unstable and 13% were dysplastic based on FHC, most Graf IIa hips had normal or borderline FHC per the AUC and may do well with observation and follow-up ultrasound at 12 weeks old.

Level of Evidence:

Level III—diagnostic study.
Anterior Cervical Corpectomy and Fusion for Degenerative Cervical Spondylotic Myelopathy
Authors: Louie Philip K. , Nemani Venu M. , Leveque Jean-Christophe A.
Published: November 2022

Anterior cervical corpectomy and fusion (ACCF) provides an extensive decompression and provides a large surface area for fusion in patients presenting with cervical spondylotic myelopathy. Unfortunately, this procedure is a more difficult spinal surgery to perform (compared with a traditional anterior cervical discectomy and fusion) and has a higher incidence of overall complications. In literature, ACCF has functional outcomes that seem clinically equivalent to those for multilevel anterior cervical discectomy and fusion, especially when contained to 1 vertebral body level, and in cases, for which both posterior and anterior procedures would be appropriate surgical options, may provide greater long-term clinical benefit than posterior fusion or laminoplasty. In this manuscript, we summarize the indications and outcomes following ACCF for degenerative cervical spondylotic myelopathy. We then describe a case presentation and associated surgical technique with a discussion of complication avoidance with this procedure.
Predictors of time-to-nadir serum creatinine after drainage of bilaterally obstructed kidneys due to bladder cancer
Authors: Gadelkareem Rabea Ahmed , Abdelraouf Ahmed Mahmoud , Ahmed Abdelfattah Ibrahim , El-Taher Ahmed Mohammed , Behnsawy Hosny Mahmoud
Published: November 2022

Background

There are persistent controversies about the outcomes and benefits of drainage of malignant ureteral obstruction by percutaneous nephrostomy (PCN). This study aimed to assess the predictors of the time-to-nadir (TTN) of serum creatinine (SCr) levels after drainage of bilaterally obstructed kidneys (BOKs) due to bladder cancer (BC) by PCN.

Materials and methods

This prospective nonrandomized study included patients with BOKs due to BC treated by PCN between April 2019 and March 2022. The primary outcome measure was TTN.

Results

Of the 55 patients with a median age (range) of 66 years (47–86 years), 32 (58.2%) had a normal nadir SCr and 23 (41.8%) had a high nadir SCr within 21 days after drainage of BOKs due to BC. High nadir SCr was associated with a higher mean age (p = 0.011) and lower body mass index (BMI, p = 0.043). However, patients with normal nadir SCr had a significantly shorter TTN (p = 0.023) and an increased mean SCr trajectory (p < 0.001) during TTN. In multivariate analysis, low urine output at presentation (p = 0.021) and high BMI (p = 0.006) were associated with longer TTN. However, the mean parenchymal thickness (p = 0.428) and laterality of drainage (p = 0.466) were not associated with the mean TTN and SCr normalization rates. According to the modified Clavien-Dindo classification, 8 cases of hematuria were managed conservatively (grade 2), and 2 cases of PCN slippage were repositioned using local anesthesia (grade 3).

Conclusions

Despite the safety of PCN for drainage of BOKs due to BC, more than 41% of the patients failed to have a normal nadir SCr. Predrainage low urine output and high BMI were associated with longer TTN. Laterality of drainage had no significant effects on the TTN and SCr trajectory.
Distributing Written Action Plans to Control Eczema Symptoms in Children
Authors: Lebedoff Karla , Bain Michelle , Walsh Susan
Published: November 2022

Written action plans for chronic diseases, such as asthma, guide parents to improve clinical outcomes for their children. Many primary care and specialty care clinicians follow national guidelines and prescribe asthma action plans annually. However, written action plans are not routinely prescribed for eczema, a chronic disease with high morbidity and prevalence that commonly presents before asthma symptoms develop. This quality improvement project initiated the use of eczema action plans with parents whose children were being managed by a pediatric dermatologist. Clinical outcomes and confidence among parents managing their child's eczema symptoms using an eczema action plan were measured. Many parents who followed individual eczema action plans reported improvement in their child's symptoms, supporting further investigation into the expected benefits of distributing eczema action plans for use at home, school, and other environments harboring potential eczema triggers.
Progress in precision therapy in pediatric oncology
Authors: O’Donohue Tara , Farouk Sait Sameer , Glade Bender Julia
Published: November 2022

Purpose of review

The fields of precision medicine and cancer genomics in pediatric oncology are rapidly evolving. Novel diagnostic tools are critical in refining cancer diagnoses, stratifying patient risk, and informing treatment decisions. This review is timely and relevant as it discusses advantages and drawbacks of common molecular profiling techniques and highlights novel platforms, which may address select limitations. We discuss recent publications demonstrating utility of large-scale molecular profiling and feasibility and logistics of matching targeted therapies to patients.

Recent findings

We describe the increased accessibility of next-generation sequencing, complementary profiling methods, and strategies to guide treatment decisions. We describe curation and sharing of large genomic datasets and novel mechanisms to obtain matched targeted therapies. Importantly, we discuss relevant publications in distinct disease domains that support indications for evidence-based precision therapy. Lastly, we introduce the incremental analyses that can be obtained via whole-genome and transcriptome sequencing.

Here we highlight high-yield clinical scenarios of precision medicine approaches and identify the ongoing challenges including universally defining clinical actionability, optimizing trial design to account for molecular heterogeneity while acknowledging limitations in patient accrual, expanding access to molecularly targeted therapies, and validating new tools and technology to aid in precision medicine therapeutic approaches.
Isolated Primary Neurolymphomatosis in the Right Brachial Plexus Proven by Partial Nerve Biopsy
Authors: Lee Gin Hoong , Hsueh Hsueh-Wen , Wang Kuo-Chuan , Yu Shan-Chi , Huang Hsin-Yi , Chao Chi-Chao , Hsieh Sung-Tsang
Published: November 2022

Introduction:

Isolated primary neurolymphomatosis is a rare manifestation of lymphoma, which is challenging to diagnose as there is only involvement of the nervous system, and nerve biopsy is not frequently pursued due to the high risk of irreversible complications.

Case Report:

We present a case of isolated primary neurolymphomatosis of diffuse large B-cell lymphoma restricted to only the right brachial plexus and right axillary nerve. The clinical course has been indolent for several years. The initial examination, including MRI and the cerebrospinal fluid study, did not yield any evidence of malignancy. Eventually, due to the patient’s symptom progression and the follow-up imaging findings, we conducted a partial nerve biopsy of the brachial plexus to confirm the malignancy. His neurological symptoms did not further deteriorate post-biopsy.

Conclusion:

Isolated primary neurolymphomatosis with an indolent course is rare and challenging to diagnose. Serial MRI and fluorodeoxyglucose-positron emission tomography reveal clues for tumor involvement. Partial nerve biopsy or targeted fascicular nerve biopsy could be an alternative for achieving a pathologic diagnosis.
Histopathologic Grading Is of Prognostic Significance in Primary Angiosarcoma of Breast
Authors: Kuba Maria G. , Dermawan Josephine K. , Xu Bin , Singer Samuel , Plitas George , Tap William D. , D’Angelo Sandra P. , Rosenbaum Evan , Brogi Edi , Antonescu Cristina R.
Published: November 2022

Despite a wide spectrum of clinical presentations, including primary or secondary, most angiosarcomas are considered high grade. One exception is primary breast angiosarcoma, where historically, histologic grading has shown to predict outcome using the Rosen 3-tier system. However, more recent studies have challenged this concept suggesting that even in this specific clinical context angiosarcomas should be considered high grade. This study aimed to critically reevaluate the impact of histologic grade in a clinically uniform cohort managed at a single institution using a newly proposed grading system. Our study included 49 primary breast angiosarcomas diagnosed during 1994 to 2022 (median follow-up: 33 mo), classified as low grade (29%), intermediate grade (20%), and high grade (51%), based on mitotic count, extent of solid components, and necrosis. At last follow-up, 22% patients developed locoregional recurrences, 63% distant metastases, and 47% patients died of disease. As patients with low and intermediate-grade angiosarcomas had relatively similar outcomes, our cohort was further analyzed using a 2-tier system (low grade and high grade). Targeted-DNA next-generation sequencing (505 cancer gene panel) performed in 11 cases found KDR mutations in 78% and PIK3CA mutations in 44% of high-grade lesions. Histologic grade, by either 3-tier or 2-tier grading systems, had a strong impact on survival, with the 2-tier system being an independent predictor of disease-specific survival and overall survival. Based on 2-tier system, the 5-year overall survival was 38% for high-grade angiosarcoma and 74% for low-grade angiosarcoma. PIK3CA mutations alone or concurrent with KDR alterations were identified in angiosarcomas with worse prognosis.
The Role of Radiolabeled Monoclonal Antibodies in Cancer Imaging and ADC Treatment
Authors: Martiniova Lucia , Zielinski Rafal J. , Lin Mai , DePalatis Louis , Ravizzini Gregory C.
Published: November 2022

Antibody-drug conjugates (ADCs) are designed to deliver cytotoxic payloads to distinctive target-expressing cancer cells. Following internalization, the ADCs are routed to different compartments in the cells, where cleavage of the linker causes release of the cytotoxic cargo. With such a delivery system, more effective payloads can reach cancer cells, allowing for more efficient treatment and dosing schedule. The monoclonal antibody (mAb) component of ADC plays a crucial role in the effective targeting of cancer cell–specific antigens while minimizing binding to normal cells. Often, the same mAbs used in ADCs can be labeled instead with radionuclides suitable for positron emission tomography or gamma-camera scintigraphy. To achieve high sensitivity and specificity for imaging, radiolabeled mAbs must have high affinity for the antigen, favorable pharmacokinetic properties, and a low toxicity profile. The use of radiolabeled mAbs permits the noninvasive interrogation of specific target expression on tumor cells and assessment of tumor heterogeneity in vivo by a simple diagnostic imaging scan that may include the whole body in the field of view. With this approach, radiolabeled mAbs can serve as important imaging biomarkers to predict the optimal delivery of ADCs to tumors and be used to monitor therapy with follow-up scans. Moreover, the same mAb can then be radiolabeled with an analogous radionuclide for the delivery of β-emitters, α-particles, or Auger electrons as part of a radioimmunotherapy approach. The purpose of this review is to introduce key concepts regarding radiolabeled mAbs targeting various tumor antigens (CD20, CDH3, type I insulinlike growth factor receptor, prostate-specific membrane antigen, and human epidermal growth factor receptor 2) that are being used in the clinical setting or undergoing development.
Toxicities From Antibody-Drug Conjugates
Authors: Johns Andrew C. , Campbell Matthew T.
Published: November 2022

Antibody-drug conjugates are becoming increasingly important in the treatment of many cancer types. The 3 main structural components—antibody, linker, and payload—each contribute to the toxicity profiles of these drugs. In addition to cytopenias and gastrointestinal adverse effects attributed to the chemotherapy payloads, each drug has specific toxicities that are not commonly described in oncology. Ocular, pulmonary, dermatologic, and neurologic toxicities are particularly nuanced. This review provides a framework for clinicians to analyze current and future antibody-drug conjugates and a description of the unique monitoring, preventive, and supportive care measures for these agents.
Antibody Drug Conjugates in Multiple Myeloma
Authors: Ferreri Christopher J. , Lee Hans C.
Published: November 2022

Antibody-drug conjugates (ADCs) have emerged as a treatment option for patients with relapsed/refractory multiple myeloma with the regulatory approval of the first-in-class B-cell maturation antigen (BCMA) ADC belantamab mafodotin. Other BCMA and non-BCMA ADCs are currently in clinical development. Whereas ADCs allow antigen-specific delivery of a chemomoiety to myeloma cells, on-target and off-target effects related to antigen target, antibody, linker, and chemomoiety can also limit these approaches. We review the clinical development of belantamab mafodotin and ongoing efforts to enhance its efficacy while mitigating ocular toxicity. The landscape of other ADCs being evaluated clinically in patients with multiple myeloma will also be reviewed.
Evolving Landscape of Antibody Drug Conjugates in Lymphoma
Authors: Prakash Rishab , Subbiah Vivek , Iyer Swaminathan P.
Published: November 2022

Despite the curative potential of autologous transplantation and chimeric antigen receptor T cells in lymphoma, many patients are ineligible, or their disease progresses after these treatments. In this context, antibody drug conjugates (ADCs) have demonstrated very promising efficacy in lymphomas. Antibody drug conjugates are monoclonal antibodies covalently linked to a cytotoxic drug. Because of its highly specific targeting abilities and powerful killing effects, it has become a promising technology for developing anticancer drugs in recent years. The US Food and Drug Administration has approved 14 ADCs since Mylotarg (gemtuzumab ozogamicin) entered the market in 2000. With advances in the design of ADCs, their efficacy and safety have moved in tandem, and many novel ADCs have gained growing interest. Three ADCs, brentuximab vedotin, polatuzumab vedotin, and loncastuximab tesirine, have been approved for treating lymphoma. The rapidly evolving ADC arsenal for treating relapsed or refractory lymphoma offers many choices. The article reviews the history and general mechanism of action of ADCs. This is followed by a discussion of the molecular aspects of their key components and their mechanisms of influence on their design and function. Finally, we review up-to-date clinical data of the approved and emerging targets of ADCs in lymphoma.
Antibody-Drug Conjugates and Tissue-Agnostic Drug Development
Authors: Dias e Silva Douglas , Andriatte Guilherme Malandrini , Pestana Roberto Carmagnani
Published: November 2022

Antibody-drug conjugates (ADCs) deliver effective medications to tumor cells that express specific antigens, maximizing efficacy and reducing adverse effects. Because ado-trastuzumab emtansine was approved in 2013, 5 ADCs received US Food and Drug Administration approval for solid tumor treatment. Technical advancements in the development of each component of ADCs allowed novel monoclonal antibodies, linkers, and payloads to increase drug transport to malignant cells and drug activity even in cancers with heterogeneous antigen expression. In addition, several ADCs are in development using new molecular targets expressed across a broad range of histologies to allow the use of ADC biomarker–driven therapy irrespective of the primary tumor site. This suggests that the future efficacy of ADCs in multiple histologies may be similar to other classes of drugs that are considered histology-agnostic therapies nowadays. This review focuses on novel ADCs for the treatment of solid tumors, including topics such as their structure and mechanism of action, the latest indications of already US Food and Drug Administration–approved ADCs, and the outlook for new promising ADCs under development for the treatment of tumors of various histologies.
APELIN-13 AMELIORATES LPS-INDUCED ENDOTHELIAL-TO-MESENCHYMAL TRANSITION AND POST–ACUTE LUNG INJURY PULMONARY FIBROSIS BY SUPPRESSING TRANSFORMING GROWTH FACTOR-Β1 SIGNALING
Authors: Liu Huang , Shi Qingqiang , Tang Ling , Wang Hanghang , Wang Daoxin
Published: November 2022

The pathophysiology of acute respiratory distress syndrome (ARDS) involves cytokine storms, alveolar-capillary barrier destruction, and fibrotic progression. Pulmonary interstitial fibrosis is an important factor affecting the prognosis of ARDS patients. Endothelial-to-mesenchymal transition (EndMT) plays an important role in the development of fibrotic diseases, and the occurrence of EndMT has been observed in experimental models of LPS-induced acute lung injury (ALI). Apelin is an endogenous active polypeptide that plays an important role in maintaining endothelial cell homeostasis and inhibiting fibrotic progression in various diseases. However, whether apelin attenuates EndMT in ALI and post-ALI pulmonary fibrosis remains unclear. We analyzed the serum levels of apelin-13 in patients with sepsis-associated ARDS to examine its possible clinical value. A murine model of LPS-induced pulmonary fibrosis and an LPS-challenged endothelial cell injury model were used to analyze the protective effect and underlying mechanism of apelin-13. Mice were treated with apelin-13 by i.p. injection, and human pulmonary microvascular endothelial cells were incubated with apelin-13 in vitro. We found that the circulating apelin-13 levels were significantly elevated in sepsis-associated ARDS patients compared with healthy controls. Our study also confirmed that LPS induced EndMT progression and pulmonary fibrosis, which were characterized by decreased CD31 expression and increased α-smooth muscle actin expression and collagen deposition. LPS also stimulated the production of transforming growth factor β1 and activated the Smad signaling pathway. However, apelin-13 treatment significantly attenuated these changes. Our findings suggest that apelin-13 may be a novel biomarker in patients with sepsis-associated ARDS. These results demonstrate that apelin-13 ameliorates LPS-induced EndMT and post-ALI pulmonary fibrosis by suppressing transforming growth factor β1 signaling.
LEUKOCYTE PHENOTYPING IN SEPSIS USING OMICS, FUNCTIONAL ANALYSIS, AND IN SILICO MODELING
Authors: Langston Jordan C. , Yang Qingliang , Kiani Mohammad F. , Kilpatrick Laurie E.
Published: November 2022

Sepsis is a major health issue and a leading cause of death in hospitals globally. The treatment of sepsis is largely supportive, and there are no therapeutics available that target the underlying pathophysiology of the disease. The development of therapeutics for the treatment of sepsis is hindered by the heterogeneous nature of the disease. The presence of multiple, distinct immune phenotypes ranging from hyperimmune to immunosuppressed can significantly impact the host response to infection. Recently, omics, biomarkers, cell surface protein expression, and immune cell profiles have been used to classify immune status of sepsis patients. However, there has been limited studies of immune cell function during sepsis and even fewer correlating omics and biomarker alterations to functional consequences. In this review, we will discuss how the heterogeneity of sepsis and associated immune cell phenotypes result from changes in the omic makeup of cells and its correlation with leukocyte dysfunction. We will also discuss how emerging techniques such as in silico modeling and machine learning can help in phenotyping sepsis patients leading to precision medicine.
THE IMMUNOPATHOGENESIS OF POLYMICROBIAL SEPSIS
Authors: Zetoune Firas S. , Ward Peter A.
Published: November 2022

This report deals with the advances made in the areas of complement and its role in sepsis, both in mice and in humans. The study relates to work over the past 25 years (late 1990s to October 2022). During this period, there has been very rapid progress in understanding the activation pathways of complement and the activation products of complement, especially the anaphylatoxin C5a and its receptors, C5aR1 and C5aR2. Much has also been learned about these pathways of activation that trigger activation of the innate immune system and the array of strong proinflammatory cytokines that can cause cell and organ dysfunction, as well as complement products that cause immunosuppression. The work in septic humans and mice, along with patients who develop lung dysfunction caused by COVID-19, has taught us that there are many strategies for treatment of humans who are septic or develop COVID-19–related lung dysfunction. To date, treatments in humans with these disorders suggest that we are in the midst of a new and exciting area related to the complement system.
A Threshold Criteria for Seasonal Amplification and Outbreaks of Mosquito-Borne Disease (MBD) Cases in Kerala using Climate Parameters
Authors: Chattopadhyay Rajib , Surendran Divya , Lekshmi S , Guhathakurta Pulak , Hosaliker K.S. , Pai D.S. , Manu M. S , Mohapatra M.
Published: November 2022

Modelling the dynamics of mosquito borne disease (MBD) cases is a challenging task. The current study first proposes a generic dynamical model to qualitatively understand the seasonality as well as outbreaks of malaria and dengue over the state of Kerala based on a climate forced oscillator model, which is then supplemented by a data driven model for quantitative evaluation. The proposed forced oscillator model is parametric and general in nature which can be qualitatively used to understand the seasonality and outbreaks. However, since parametric model-based estimation require estimation of multiple parameters and several closure assumptions, we used the K-means clustering which is a data driven clustering approach to understand the relationship between Malaria and Dengue cases and climate forcing. The results showed a clear relationship of the MBD cases with the first order and second order moments (i.e. mean and standard deviation) of the climate forcing parameters. Based on this, we came up with an objective threshold criterion which relates the climate parameters to the number of cases of malaria and dengue cases over Kerala.
The PBL teaching method in Neurology Education in the Traditional Chinese Medicine undergraduate students: An Observational Study
Authors: Kim Yun Jin
Published: November 2022

Objective

To study the effect of the Problem Based Learning method in Neurology education for Traditional Chinese Medicine (TCM) undergraduate students.

Methods

In this observational study was conducted 2020/02 and 2020/04 intake the year three TCM undergraduate students of the School of Traditional Chinese Medicine, Xiamen University Malaysia. A total of 86 were enrolled in this study. They were randomly divided into conventional learning groups and PBL groups. Students who missed more than one session of the course and those who did not complete the questionnaires in the evaluation periods were excluded from the study (n=0). An independent sample t-test was used to compare the results between the two groups. A p-value <0.05 was considered significant.

Results

The PBL group was significantly effective for the students’ theoretical and clinical practical examination scores, the satisfaction of teaching level, students’ perspectives, and self-learning skills, as well as significantly higher DREEM scores than students who participated with the conventional group (p<0.05).

Conclusion

The PBL teaching method in Neurology education for TCM undergraduate students can involve an interesting learning method, significantly improve their learning performance, and the ability to analyze the problem-solving skills in the neurology disease and its management knowledge.
Genome-wide association study highlights escape from aphids by delayed growth inArabidopsis thaliana
Authors: Xu Chongmeng , Sato Yasuhiro , Yamazaki Misako , Brasser Marcel , Barbour Matthew A. , Bascompte Jordi , Shimizu Kentaro K.
Published: November 2022

Field studies have shown that plant phenological and architectural traits often explain substantial variation in herbivory. Although plant genes involved in physical and chemical defense are well studied, less is known about the genetic basis underlying effects of plant growth traits on herbivory. Here, we conducted a genome-wide association study (GWAS) of aphid abundance in a field population ofArabidopsis thaliana. This field GWAS detected a significant peak on the third chromosome ofA. thaliana. Out of candidate genes near this significant genomic region, a mutant of a ribosomal gene (AT3G13882) exhibited slower growth and later flowering than a wild type under laboratory conditions. A no-choice assay with the turnip aphid,Lipaphis erysimi, found that aphids were unable to successfully establish on the mutant. These findings suggest the potential role of growth-related genes in altering herbivore abundance.
DrFARM: Identification and inference for pleiotropic gene in GWAS
Authors: Chan Lap Sum , Li Gen , Fauman Eric B. , Laakso Markku , Boehnke Michael , Song Peter X.K.
Published: November 2022

In a standard analysis, pleiotropic variants are identified by running separate genome-wide association studies (GWAS) and combining results across traits. But such two-stage statistical approach may lead to spurious results. We propose a new statistical approach,Debiased-regularizedFactorAnalysisRegressionModel (DrFARM), through a joint regression model for simultaneous analysis of high-dimensional genetic variants and multilevel dependencies. This joint modeling strategy controls overall error to permit universal false discovery rate (FDR) control. DrFARM uses the strengths of the debiasing technique and the Cauchy combination test, both being theoretically justified, to establish a valid post selection inference on pleiotropic variants. Through extensive simulations, we show that DrFARM appropriately controls overall FDR. Applying DrFARM to data on 1,031 metabolites measured on 6,135 men from the Metabolic Syndrome in Men (METSIM) study, we identify 288 new metabolite associations at loci that did not reach statistical significance in prior METSIM metabolite GWAS.
Molecular evolution of non-visual opsin genes across environmental, developmental, and morphological adaptations in frogs
Authors: Boyette John L , Bell Rayna C , Fujita Matthew K , Thomas Kate N , Streicher Jeffrey W , Gower David J , Schott Ryan K
Published: November 2022

Non-visual opsins are transmembrane proteins expressed in the eyes, skin, and brain of many animals. When paired with a light-sensitive chromophore, non-visual opsins form photopigment systems involved in various non-visual, light-detection functions, including circadian rhythm regulation, light-seeking behavior, and detection of seasonality. Previous research has primarily explored the diversity and function of non-visual opsins in model organisms, with few studies investigating their molecular evolution in non-model species. Here we explored molecular evolution of non-visual opsin genes in anuran amphibians (frogs and toads). With diverse lifestyles ranging from fossorial to aquatic, anurans inhabit a diverse array of light environments, which makes them a compelling system for studying the evolution of light detection mechanisms. Using whole-eye transcriptomes from 79 anuran species, as well as genomes and multi-tissue transcriptomes from an additional 15 species, we 1) identify which non-visual opsin genes are expressed in the eyes of anurans; 2) compare selective constraint (ω, or dN/dS) among non-visual opsin genes; and 3) test for potential adaptive evolution by comparing selection between discrete ecological classes in anurans (e.g. diurnal versus non-diurnal). We consistently recovered 14 non-visual opsin genes from anuran eye transcriptomes, compared to 18 genes that we recovered genome wide, and detected positive selection in a subset of these genes. We also found variation in selective constraint between discrete ecological and life-history classes, which may reflect functional adaptation in non-visual opsin genes. Although non-visual opsins remain poorly understood, these findings provide insight into their molecular evolution and set the stage for future research on their potential function across taxa with diverse environmental, developmental, and morphological adaptations.
A consensus score to combine inferences from multiple centres
Authors: Haselimashhadi Hamed , Babalola Kolawole , Wilson Robert , Groza Tudor , Muñoz-Fuentes Violeta
Published: November 2022

Experiments in which data are collected by multiple independent resources, including multicentre data, different laboratories within the same centre or with different operators, are challenging in design, data collection and interpretation. Indeed, inconsistent results across the resources are possible. In this paper, we propose a statistical solution for the problem of multi-resource consensus inferences when statistical results from different resources show variation in magnitude, directionality, and significance. Our proposed method allows combining the corrected p-values, effect sizes and the total number of centres into a global consensus score. We apply this method to obtain a consensus score for data collected by the International Mouse Phenotyping Consortium (IMPC) across 11 centres. We show the application of this method to detect sexual dimorphism in haematological data and discuss the suitability of the methodology.
A Bioinformatic Study of the Distribution of Mn Oxidation Proteins in Sequenced Bacterial Genomes
Authors: Kurdi M. Zakaria , Olichney Jacob , Geszvain Kati
Published: November 2022

1.

Background

While many species of bacteria have been identified that can convert soluble, reduced manganese (Mn+2) into insoluble, oxidized Mn+4oxides, the mechanisms these bacteria employ and their distribution throughout the bacterial domain are less well understood. One of the best characterized MnOB is the gamma-proteobacteriumPseudomonas putidaGB-1, which uses three distinct proteins (PpMnxG, McoA and MopA) to oxidize Mn+2. The best characterized Mn oxidase enzyme is the MnxG homolog ofBacillussp. PL-12 (BaMnxG), which appears to be the only Mn oxidase in this species. MofA, found inLeptothrix discophorasp SS-1 is an additional putative Mn oxidase.

Results

By querying publicly available databases of bacterial genome sequences for homologs to these Mn oxidase proteins, it was possible to determine the distribution of the proteins within bacteria. The overwhelming majority of homologs were found in just three phyla: proteobacteria, actinobacteria and firmicutes. These data do not preclude the possibility of novel Mn oxidase mechanisms in other as yet uncharacterized groups of bacteria. Each of the homologs had a statistically significant probability of being present as the solo Mn oxidase in a genome. When genomes did have more than one oxidase, they were present in the same combinations as inP. putidaGB-1.

Conclusions

These results do not support the initial hypothesis that multiple enzymes are required to complete the two-electron oxidation of Mn+2to Mn+4. Alternatively, the various Mn oxidase enzymes may be optimized to function under different environmental conditions; organisms likeP. putidaGB-1 may need to oxidize Mn at different temperatures, nutritional states or oxygen conditions.
Accuracy of a markerless motion capture system for balance related quantities
Authors: Chaumeil Anaïs , Lahkar Bhrigu Kumar , Dumas Raphaël , Muller Antoine , Robert Thomas
Published: November 2022

Background

Balance studies usually focus on quantities describing the global body motion, such as the position of the whole-body centre of mass (CoM), its associated extrapolated centre of mass (XCoM) and the whole-body angular momentum (WBAM). Assessing such quantities using classical marker-based approach can be tedious and modify the participant’s behaviour. The recent development of markerless motion capture methods could bypass the issues related to the use of markers.

Research question

Can we use markerless motion capture systems to study quantities that are relevant for balance studies?

Methods

Sixteen young healthy participants performed four different motor tasks: walking at self-selected speed, balance loss, walking on a narrow beam and countermovement jumps. Their movements were recorded simultaneously by marker-based and markerless motion capture systems. Videos were processed using a commercial markerless pose estimation software, Theia3D. The position of their CoM was computed, and the associated XCoM and WBAM were derived. Bland-Altman analysis was performed and root mean square error and coefficient of determination were computed to compare the results obtained with marker-based and markerless methods across all participants and tasks.

Results

Bias remained of the magnitude of a few mm for CoM and XCoM position, and RMSE of CoM and XCoM was around 1 cm. Confidence interval for CoM and XCoM was under 2 cm except for one task in one direction. RMSE of the WBAM was less than 8% of the total amplitude in any direction, and bias was less than 1%.

Significance

Results suggest that the markerless motion capture system can be used in balance studies as the measured errors are in the range of the differences found between different models or populations in the literature. Nevertheless, one should be careful when assessing dynamic movements such as jumping, as they displayed the biggest errors.

Highlights

Markerless motion capture could bypass issues from classical marker-based approaches

We compared balance related quantities computed from both approaches

Mean differences were about 1cm on the position of the whole-body center of mass

Obtained differences are acceptable for most applications
Environmental stress during larval development induces head methylome profile shifts in the migratory painted lady butterfly (Vanessa cardui)
Authors: Boman Jesper , Zhu Yishu , Höök Lars , Vila Roger , Talavera Gerard , Backström Niclas
Published: November 2022

Seasonal environmental fluctuations provide formidable challenges for living organisms, especially small ectotherms such as butterflies. A common strategy to cope with harsh environments is to enter diapause, but some species avoid the unsuitable conditions by migrating. Despite a growing understanding of migration in the life cycles of some butterfly species, it is unknown how individuals register and store environmental cues to determine whether and where to migrate. Here, we explored how competition and host plant availability during larval development affect patterns of DNA methylation in the migratory painted lady (Vanessa cardui) butterfly. We identify a set of potentially functional methylome shifts associated with differences in the environment, indicating that DNA methylation is involved in the response to different conditions during larval development. By analysing the transcriptome for the same samples used for methylation profiling, we also uncovered a non-linear relationship between gene body methylation and gene expression. Our results provide a starting point for understanding the interplay between DNA methylation and gene expression in butterflies in general and how differences in environmental conditions during development can trigger unique epigenetic marks that might be important for behavioural decisions in the adult stage.
Reconciliation and evolution ofPenicillium rubensGenome-Scale Metabolic Networks – What about specialised metabolism?
Authors: Nègre Delphine , Larhlimi Abdelhalim , Bertrand Samuel
Published: November 2022

In recent years, genome sequencing of filamentous fungi has revealed a high proportion of specialised metabolites with growing pharmaceutical interest. However, detecting such metabolites throughin silicogenome analysis does not necessarily guarantee their expression under laboratory conditions. However, one plausible strategy for enabling their production lies in modifying the growth conditions. Devising a comprehensive experimental design testing in different culture environments is time-consuming and expensive. Therefore, usingin silicomodelling as a preliminary step, such as Genome-Scale Metabolic Network (GSMN), represents a promising approach to predicting and understanding the observed specialised metabolite production in a given organism. To address these questions, we reconstructed a new high-quality GSMN for thePenicillium rubensWisconsin 54-1255 strain, a commonly used model organism. Our reconstruction,iPrub22, adheres to current convention standards and quality criteria, incorporating updated functional annotations, orthology searches with different GSMN templates, data from previous reconstructions, and manual curation steps targeting primary and specialised metabolites. With a MEMOTE score of 74% and a metabolic coverage of 45%,iPrub22 includes 5,192 unique metabolites interconnected by 5,919 reactions, of which 5,033 are supported by at least one genomic sequence. Of the metabolites present iniPrub22, 13% are categorised as belonging to specialised metabolism. While our high-quality GSMN provides a valuable resource for investigating known phenotypes expressed inP. rubens, our analysis identifies bottlenecks related, in particular, to the definition of what is a specialised metabolite, which requires consensus within the scientific community. It also points out the necessity of accessible, standardised and exhaustive databases of specialised metabolites. These questions must be addressed to fully unlock the potential of natural product production inP. rubensand other filamentous fungi. Our work represents a foundational step towards the objective of rationalising the production of natural products through GSMN modelling.