Role of Supplemental Breast MRI in Screening Women with Mammographically Dense Breasts: A Systematic Review and Meta-analysis.

BACKGROUND: High mammographic density increases breast cancer risk and reduces mammographic sensitivity. We reviewed evidence on accuracy of supplemental MRI for women with dense breasts at average or increased risk. METHODS: PubMed and Embase were searched 1995-2022. Articles were included if women received breast MRI following 2D or tomosynthesis mammography. Risk of bias was assessed using QUADAS-2. Analysis used independent studies from the articles. Fixed-effect meta-analytic summaries were estimated for predefined groups (PROSPERO: 230277). RESULTS: Eighteen primary research articles (24 studies) were identified in women aged 19-87 years. Breast density was heterogeneously or extremely dense (BI-RADS C/D) in 15/18 articles and extremely dense (BI-RADS D) in 3/18 articles. Twelve of 18 articles reported on increased-risk populations. Following 21 440 negative mammographic examinations, 288/320 cancers were detected by MRI. Substantial variation was observed between studies in MRI cancer detection rate, partly associated with prevalent vs incident MRI exams (prevalent: 16.6/1000 exams, 12 studies; incident: 6.8/1000 exams, 7 studies). MRI had high sensitivity for mammographically occult cancer (20 studies with at least 1-year follow-up). In 5/18 articles with sufficient data to estimate relative MRI detection rate, approximately 2 in 3 cancers were detected by MRI (66.3%, 95% CI, 56.3%-75.5%) but not mammography. Positive predictive value was higher for more recent studies. Risk of bias was low in most studies. CONCLUSION: Supplemental breast MRI following negative mammography in women with dense breasts has breast cancer detection rates of ~16.6/1000 at prevalent and ~6.8/1000 at incident MRI exams, considering both high and average risk settings.

Corrigendum: Unraveling the dynamics of wheat leaf blight complex: isolation, characterization, and insights into pathogen population under Indian conditions.

[This corrects the article DOI: 10.3389/fmicb.2024.1287721.].

Unraveling the dynamics of wheat leaf blight complex: isolation, characterization, and insights into pathogen population under Indian conditions.

Wheat, a staple food crop for 35% of the global population, faces a threat from Helminthosporium leaf blight (HLB), a complex of spot blotch (Bipolaris sorokiniana) and tan spot (Pyrenophora-tritici-repentis) diseases under warm and humid conditions. However, in Indian conditions, the knowledge of existing pathogen populations associated with the HLB complex is limited and largely dominated by only B. sorokiniana (spot blotch). To address this, diseased samples were collected from all six wheat growing zones during 2020-2022. The pathogenic species were identified through in-depth morphological characterization, supplemented with ITS-rDNA and GAPDH sequence analysis, a diagnostic SCAR marker, and pathogenicity studies on two wheat varieties: Sonalika and HD2733. The 32 isolates collected from 10 different states consist of B. spicifera (12.5% of all isolates), Exserohilum rostratum (9.3%), Bipolaris oryzae (3.1%), and B. sorokiniana (75%). B. sorokiniana exhibited the highest disease severity on both varieties. Other lesser-known pathogenic species also produced comparable disease severity as B. sorokiniana isolates and, therefore are economically important. Unraveling pathogen composition and biology aids in disease control and resistance breeding. Our study highlights economically impactful and lesser-known pathogenic species causing wheat leaf blight/spot blotch in India, guiding both current management and future resistance breeding strategies in plant pathology.

Isolated perinephric abscess as the initial manifestation of filariasis-an unusual presentation.

Key Clinical Message: Filariasis may present as an isolated perinephric abscess. Hence, a high index of suspicion should be maintained in endemic settings. Abstract: In cases with unexplained fever, eosinophilia and perinephric collection, it is necessary to do detailed infectious disease work up. High index of suspicion is required to diagnose filariasis due to its wide range of clinical presentation and laboratory findings. It may present as perinephric abscess, which can be diagnosed through ultrasonography.

Osteochondroma of the atlas vertebra causing high grade spinal canal stenosis: a rare case report.

Osteochondromas are the most common primary benign bone tumors which can be either solitary or multiple in the form of hereditary multiple exostosis (HME). Osteochondromas are located frequently in the long bones and rarely involve the spine. Cervical spine remains the most common site for spinal osteochondroma. However, majority of the cases are neurologically asymptomatic as most of them are slow growing with growth directed outside the spinal canal. In this case report, we describe a rare case of solitary osteochondroma arising from C1 vertebra (atlas) resulting in serious neurological complications, ultimately necessitating surgical intervention.

High-Quality Genome Resource of Ustilaginoidea virens (UV2_4G), Causal Agent of an Emerging False Smut Disease in Rice.

Ustilaginoidea virens is the fungal pathogen causing an emerging false smut disease that affects crop yield as well as deteriorates quality of the grains by producing mycotoxins. A high quality genome of U. virens isolate UV2_4G was sequenced using Nanopore and Illumina HiSeq 2,000 sequencing platforms. The total assembled genome of Indian isolate UV2_4G was 35.9 Mb, which comprised 89 scaffolds with N50 of 700,296 bp. A total of 358,697 variants were identified in the genome, out of which 355,173 were SNPs and 3,524 were INDELS. Further, 7,390 SSRs belonging to different repeat types were also identified in the genome. Out of 7,444 proteins predicted, 7,206 were functionally annotated. A total of 1,307 CAZymes, 501 signal peptides, 1,876 effectors, and 2,709 genes involved in host-pathogen interactions were identified. Comparative analysis revealed isolate UV2_4G is distinct with 31 unique clusters and placed distantly in phylogenetic analysis. Taken together, this high-quality genome assembly and sequence annotation resource can give an improved insight for characterizing the biological and pathogenic mechanisms of U. virens.

Formulation and Characterization of Losartan Loaded Chitosan Microspheres: Effect of Crosslinking Agents.

OBJECTIVE: The present investigation entailed determination of effect of diverse cross-linking agents on Losartan Potassium loaded chitosan microspheres. The emulsion cross-linking method was employed to formulate the microspheres with an endeavour to achieve maximum sustained effect. METHODS: The FTIR studies revealed absence of any interaction between Losartan and chitosan. The emulsion cross linking method was accomplished in three steps encompassing formation of an aqueous and oily phase, emulsification and cross-linking. A total of eighteen Losartan formulations were developed using six different cross-linkers at three varying level were screened for optimum parameters. The in vitro drug release parameters of optimum formulations (LC3, LE3, LF3, LG3, LS3 and LV3) containing citric acid, epichlorohydrin, formaldehyde, glutaraldehyde, suphuric acid and vanillin as cross-linkers were assessed to determine the sustained effect. RESULTS: The values of evaluated parameters including percent yield (94.67%), average particle size (51.19 µm), drug content (44.38 mg) and entrapment efficiency (88.77%) connoted LG3 as the best formulation. Additionally, the values of relative measure of skewness (ß1=0.01 and γ1=0.10) and platykurtic (ß2=1.26) size distribution were least for LG3 with spherical shape and smooth surface as revealed by SEM studies. CONCLUSION: The outcome of in vitro release and other characterizations of microspheres explicitly revealed glutaraldehyde as the best cross-linker amongst the cross-linkers used herewith. The maximum sustained effect (lasting over a period of 24 h) accompanied with higher MDT and t50% with lower%DE and Q14h values thus corroborated the objective of attaining sustained release of Losartan.

The Lack of WIP Binding to Actin Results in Impaired B Cell Migration and Altered Humoral Immune Responses.

Wiskott-Aldrich syndrome protein (WASp) is a main cytoskeletal regulator in B cells. WASp-interacting protein (WIP) binds to and stabilizes WASp but also interacts with actin. Using mice with a mutated actin binding domain of WIP (WIPΔABD), we here investigated the role of WIP binding to actin during B cell activation. We found an altered differentiation of WIPΔABD B cells and diminished antibody affinity maturation after immunization. Mechanistically, WIPΔABD B cells showed impaired B cell receptor (BCR)-induced PI3K signaling and actin reorganization, likely caused by diminished CD81 expression and altered CD19 dynamics on the B cell surface. WIPΔABD B cells displayed reduced in vivo motility, concomitantly with impaired chemotaxis and defective F-actin polarization, HS1 phosphorylation, and polarization of HS1 to F-actin-rich structures after CXCL12 stimulation in vitro. We thus concluded that WIP binding to actin, independent of its binding to WASp, is critical for actin cytoskeleton plasticity in B cells.

Tuning of in vivo cognate B-T cell interactions by Intersectin 2 is required for effective anti-viral B cell immunity.

Wiskott-Aldrich syndrome (WAS) is an immune pathology associated with mutations in WAS protein (WASp) or in WASp interacting protein (WIP). Together with the small GTPase Cdc42 and other effectors, these proteins participate in the remodelling of the actin network downstream of BCR engagement. Here we show that mice lacking the adaptor protein ITSN2, a G-nucleotide exchange factor (GEF) for Cdc42 that also interacts with WASp and WIP, exhibited increased mortality during primary infection, incomplete protection after Flu vaccination, reduced germinal centre formation and impaired antibody responses to vaccination. These defects were found, at least in part, to be intrinsic to the B cell compartment. In vivo, ITSN2 deficient B cells show a reduction in the expression of SLAM, CD84 or ICOSL that correlates with a diminished ability to form long term conjugates with T cells, to proliferate in vivo, and to differentiate into germinal centre cells. In conclusion, our study not only revealed a key role for ITSN2 as an important regulator of adaptive immune-response during vaccination and viral infection but it is also likely to contribute to a better understanding of human immune pathologies.

Initiation of Antiviral B Cell Immunity Relies on Innate Signals from Spatially Positioned NKT Cells.

B cells constitute an essential line of defense from pathogenic infections through the generation of class-switched antibody-secreting cells (ASCs) in germinal centers. Although this process is known to be regulated by follicular helper T (TfH) cells, the mechanism by which B cells initially seed germinal center reactions remains elusive. We found that NKT cells, a population of innate-like T lymphocytes, are critical for the induction of B cell immunity upon viral infection. The positioning of NKT cells at the interfollicular areas of lymph nodes facilitates both their direct priming by resident macrophages and the localized delivery of innate signals to antigen-experienced B cells. Indeed, NKT cells secrete an early wave of IL-4 and constitute up to 70% of the total IL-4-producing cells during the initial stages of infection. Importantly, the requirement of this innate immunity arm appears to be evolutionarily conserved because early NKT and IL-4 gene signatures also positively correlate with the levels of neutralizing antibodies in Zika-virus-infected macaques. In conclusion, our data support a model wherein a pre-TfH wave of IL-4 secreted by interfollicular NKT cells triggers the seeding of germinal center cells and serves as an innate link between viral infection and B cell immunity.

dbGAPs: A comprehensive database of genes and genetic markers associated with psoriasis and its subtypes.

Psoriasis is a systemic hyperproliferative inflammatory skin disorder, although rarely fatal but significantly reduces quality of life. Understanding the full genetic component of the disease association may provide insight into biological pathways as well as targets and biomarkers for diagnosis, prognosis and therapy. Studies related to psoriasis associated genes and genetic markers are scattered and not easily amendable to data-mining. To alleviate difficulties, we have developed dbGAPs an integrated knowledgebase representing a gateway to psoriasis associated genomic data. The database contains annotation for 202 manually curated genes associated with psoriasis and its subtypes with cross-references. Functional enrichment of these genes, in context of Gene Ontology and pathways, provide insight into their important role in psoriasis etiology and pathogenesis. The dbGAPs interface is enriched with an interactive search engine for data retrieval along with unique customized tools for Single Nucleotide Polymorphism (SNP)/indel detection and SNP/indel annotations. dbGAPs is accessible at http://www.bmicnip.in/dbgaps/.

A switch from canonical to noncanonical autophagy shapes B cell responses.

Autophagy is important in a variety of cellular and pathophysiological situations; however, its role in immune responses remains elusive. Here, we show that among B cells, germinal center (GC) cells exhibited the highest rate of autophagy during viral infection. In contrast to mechanistic target of rapamycin complex 1-dependent canonical autophagy, GC B cell autophagy occurred predominantly through a noncanonical pathway. B cell stimulation was sufficient to down-regulate canonical autophagy transiently while triggering noncanonical autophagy. Genetic ablation of WD repeat domain, phosphoinositide-interacting protein 2 in B cells alone enhanced this noncanonical autophagy, resulting in changes of mitochondrial homeostasis and alterations in GC and antibody-secreting cells. Thus, B cell activation prompts a temporal switch from canonical to noncanonical autophagy that is important in controlling B cell differentiation and fate.

Tuberous breast deformity: A modified technique for single-stage correction.

INTRODUCTION: Tuberous breast deformity is one of the most challenging congenital breast anomalies. Severe forms present as hypoplasia of lower medial and lateral quadrants and breast base constriction. We present a modified technique based on redistribution of breast tissue for single-stage aesthetic correction of this deformity. MATERIAL METHODS AND SURGICAL TECHNIQUE: The technique is based on Lejour's method of single vertical scar breast reduction. The breast tissue is divided into three superiorly based pedicles. However, instead of joining the three pedicles, they are spread to redistribute tissue to quadrants which are deficient. This technique is combined with implant insertion if the breast volume is deficient or mastopexy if there is significant ptosis. The level of nipples is matched to achieve symmetry and areolar reduction done where indicated. We have used this for six patients with Type I/II/III (von Heimburg, 2000) tuberous breast deformity. RESULTS AND DISCUSSION: The aesthetic results have been very good in terms of shape, volume, symmetry and patient satisfaction. A historical summary of the development of techniques for correction of tuberous breast is presented along with description of our method and its results.

Current Practice of Therapeutic Mammaplasty: A Survey of Oncoplastic Breast Surgeons in England.

INTRODUCTION: Therapeutic mammaplasty (TM) is a useful technique in the armamentarium of the oncoplastic breast surgeon (OBS). There is limited guidance on patient selection, technique, coding, and management of involved margins. The practices of OBS in England remain unknown. METHODS: Questionnaires were sent to all OBS involved with the Training Interface Group. We assessed the number of TM cases performed per surgeon, criteria for patient selection, pedicle preference, contralateral symmetrisation, use of routine preoperative MRI, management of involved margins, and clinical coding. RESULTS: We had an overall response rate of 43%. The most common skin resection technique utilised was wise pattern followed by vertical scar. Superior-medial pedicle was preferred by the majority of surgeons (62%) followed by inferior pedicle (34%). Twenty percent of surgeons would always proceed to a mastectomy following an involved margin, whereas the majority would offer reexcision based on several parameters. The main absolute contraindication to TM was tumour to breast ratio >50%. One in five surgeons would not perform TM in smokers and patients with multifocal disease. DISCUSSION: There is a wide variation in the practice of TM amongst OBS. Further research and guidance would be useful to standardise practice, particularly management of involved margins and coding for optimal reimbursement.

Probing binding mechanism of interleukin-6 and olokizumab: in silico design of potential lead antibodies for autoimmune and inflammatory diseases.

Computer-aided antibody engineering has been successful in the design of new biologics for disease diagnosis and therapeutic interventions. Interleukin-6 (IL-6), a well-recognized drug target for various autoimmune and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, and psoriasis, was investigated in silico to design potential lead antibodies. Here, crystal structure of IL-6 along with monoclonal antibody olokizumab was explored to predict antigen-antibody (Ag - Ab)-interacting residues using DiscoTope, Paratome, and PyMOL. Tyr56, Tyr103 in heavy chain and Gly30, Ile31 in light chain of olokizumab were mutated with residues Ser, Thr, Tyr, Trp, and Phe. A set of 899 mutant macromolecules were designed, and binding affinity of these macromolecules to IL-6 was evaluated through Ag - Ab docking (ZDOCK, ClusPro, and Rosetta server), binding free-energy calculations using Molecular Mechanics/Poisson Boltzman Surface Area (MM/PBSA) method, and interaction energy estimation. In comparison to olokizumab, eight newly designed theoretical antibodies demonstrated better result in all assessments. Therefore, these newly designed macromolecules were proposed as potential lead antibodies to serve as a therapeutics option for IL-6-mediated diseases.

The TeaM (Therapeutic Mammaplasty) study: Protocol for a prospective multi-centre cohort study to evaluate the practice and outcomes of therapeutic mammaplasty.

INTRODUCTION: Wide local excision and adjuvant radiotherapy is the standard of care for early breast cancer. For large tumours, however, mastectomy is frequently recommended as conventional breast-conserving techniques often result in poor cosmetic outcomes. Therapeutic mammaplasty (TM) may extend the boundaries of breast-conserving surgery by combining breast reduction and mastopexy techniques with tumour excision, preserving a natural breast shape and avoiding the need for mastectomy. The prevalence of this operative option among surgeons in the UK and its success rate are unknown. The TeaM study is a multicentre prospective study that aims to investigate the practice and outcomes of TM. METHODS AND ANALYSIS: Breast centres performing TM will be invited to participate through the research collaborative network and the professional associations. All patients undergoing TM between September 2016 and March 2017 will be included. Demographic, operative, oncological and complication data within 30-days of surgery will be collected. The primary outcome will be unplanned re-operation for complications. Secondary outcomes will include unplanned readmission, re-excision rates and time to adjuvant therapy. Prospective data on 500 patients from 50 centres are anticipated. Exploratory analyses will identify predictors for complications and inform the design of a definitive study. ETHICS AND DISSEMINATION: Research ethics approval is not required for this study. This has been confirmed by the on-line Health Research Authority decision tool. This study will provide novel information regarding the practice and outcomes of TM in the UK. This will inform decision-making for patients and surgeons and inform future research. Dissemination of the study protocol will be via the Mammary Fold Academic and Research Collaborative, the Reconstructive Surgery Trials Network and the professional associations, the Association of Breast Surgery and British Association of Plastic, Reconstructive and Aesthetic Surgeons. Results will be presented at relevant surgical conferences and published in peer-reviewed journals.

Orocutaneous Fistula or Traumatic Infectious Skin Lesion: A Diagnostic Dilemma.

Orocutaneous fistula (OCF) (of dental origin) is an uncommon but well-described condition in the literature. These are often misdiagnosed by physicians and dentists. Careful selection of investigating modality is important in case of diagnostically challenging cases. A 19-year-old female came with a complaint of a lesion on the chin reported with h/o trauma with the impact on chin presented as diagnostic dilemma because of unusual case history and clinical examination. Commonly used radiographic investigations like IOPA and orthopantomograph did not resolve the dilemma whereas advanced imaging modality like CT scan, 3D volume imaging, and contrast enhanced CT played an important role in the diagnosis of OCF and selecting the treatment plan.

Wiskott-Aldrich Syndrome Interacting Protein Deficiency Uncovers the Role of the Co-receptor CD19 as a Generic Hub for PI3 Kinase Signaling in B Cells.

Humans with Wiskott-Aldrich syndrome display a progressive immunological disorder associated with compromised Wiskott-Aldrich Syndrome Interacting Protein (WIP) function. Mice deficient in WIP recapitulate such an immunodeficiency that has been attributed to T cell dysfunction; however, any contribution of B cells is as yet undefined. Here we have shown that WIP deficiency resulted in defects in B cell homing, chemotaxis, survival, and differentiation, ultimately leading to diminished germinal center formation and antibody production. Furthermore, in the absence of WIP, several receptors, namely the BCR, BAFFR, CXCR4, CXCR5, CD40, and TLR4, were impaired in promoting CD19 co-receptor activation and subsequent PI3 kinase (PI3K) signaling. The underlying mechanism was due to a distortion in the actin and tetraspanin networks that lead to altered CD19 cell surface dynamics. In conclusion, our findings suggest that, by regulating the cortical actin cytoskeleton, WIP influences the function of CD19 as a general hub for PI3K signaling.

Dynamics of the Peripheral Membrane Protein P2 from Human Myelin Measured by Neutron Scattering--A Comparison between Wild-Type Protein and a Hinge Mutant.

Myelin protein P2 is a fatty acid-binding structural component of the myelin sheath in the peripheral nervous system, and its function is related to its membrane binding capacity. Here, the link between P2 protein dynamics and structure and function was studied using elastic incoherent neutron scattering (EINS). The P38G mutation, at the hinge between the ß barrel and the α-helical lid, increased the lipid stacking capacity of human P2 in vitro, and the mutated protein was also functional in cultured cells. The P38G mutation did not change the overall structure of the protein. For a deeper insight into P2 structure-function relationships, information on protein dynamics in the 10 ps to 1 ns time scale was obtained using EINS. Values of mean square displacements mainly from protein H atoms were extracted for wild-type P2 and the P38G mutant and compared. Our results show that at physiological temperatures, the P38G mutant is more dynamic than the wild-type P2 protein, especially on a slow 1-ns time scale. Molecular dynamics simulations confirmed the enhanced dynamics of the mutant variant, especially within the portal region in the presence of bound fatty acid. The increased softness of the hinge mutant of human myelin P2 protein is likely related to an enhanced flexibility of the portal region of this fatty acid-binding protein, as well as to its interactions with the lipid bilayer surface requiring conformational adaptations.

Inferring population structure and relationship using minimal independent evolutionary markers in Y-chromosome: a hybrid approach of recursive feature selection for hierarchical clustering.

Inundation of evolutionary markers expedited in Human Genome Project and 1000 Genome Consortium has necessitated pruning of redundant and dependent variables. Various computational tools based on machine-learning and data-mining methods like feature selection/extraction have been proposed to escape the curse of dimensionality in large datasets. Incidentally, evolutionary studies, primarily based on sequentially evolved variations have remained un-facilitated by such advances till date. Here, we present a novel approach of recursive feature selection for hierarchical clustering of Y-chromosomal SNPs/haplogroups to select a minimal set of independent markers, sufficient to infer population structure as precisely as deduced by a larger number of evolutionary markers. To validate the applicability of our approach, we optimally designed MALDI-TOF mass spectrometry-based multiplex to accommodate independent Y-chromosomal markers in a single multiplex and genotyped two geographically distinct Indian populations. An analysis of 105 world-wide populations reflected that 15 independent variations/markers were optimal in defining population structure parameters, such as FST, molecular variance and correlation-based relationship. A subsequent addition of randomly selected markers had a negligible effect (close to zero, i.e. 1 × 10(-3)) on these parameters. The study proves efficient in tracing complex population structures and deriving relationships among world-wide populations in a cost-effective and expedient manner.