bluuebunny/crossref_metadata_2025 huggingface dataset:
The initiation and early development of the tubulin-containing cytoskeleton in the human parasite Toxoplasma gondii
Authors: Padilla Luisa F. Arias , Murray John M. , Hu Ke
Published: January 2024

The tubulin-containing cytoskeleton of the human parasite Toxoplasma gondii includes several distinct structures: the conoid, formed of 14 ribbon-like tubulin polymers, and the array of 22 cortical microtubules (MTs) rooted in the apical polar ring. Here we analyze the structure of developing daughter parasites using both 3D-SIM and expansion microscopy. Cortical MTs and the conoid start to develop almost simultaneously, but from distinct precursors near the centrioles. Cortical MTs are initiated in a fixed sequence, starting around the periphery of a short arc that extends to become a complete circle. The conoid also develops from an open arc into a full circle, with a fixed spatial relationship to the centrioles. The patterning of the MT array starts from a “blueprint” with ∼five-fold symmetry, switching to 22-fold rotational symmetry in the final product, revealing a major structural rearrangement during daughter growth. The number of MT is essentially invariant in the wild-type array, but is perturbed by the loss of some structural components of the apical polar ring. This study provides insights into the development of tubulin-containing structures that diverge from conventional models, insights that are critical for understanding the evolutionary paths leading to construction and divergence of cytoskeletal frameworks.
Reported harassment and mental ill-health in a Canadian prospective cohort of women and men in welding and electrical trades
Authors: Galarneau Jean-Michel , Durand-Moreau Quentin , Cherry Nicola
Published: January 2024

Objectives

Experience of psychosocial environments by workers entering trade apprenticeships may differ by gender. We aimed to document perceived harassment and to investigate whether this related to mental ill-health.

Methods

Cohorts of workers in welding and electrical trades were established, women recruited across Canada and men from Alberta. Participants were recontacted every 6 months for up to 3 years (men) or 5 years (women). At each contact, they were asked about symptoms of anxiety and depression made worse by work. After their last regular contact, participants received a “wrap-up” questionnaire that included questions on workplace harassment. In Alberta, respondents who consented were linked to the administrative health database that recorded diagnostic codes for each physician contact.

Results

One thousand eight hundred and eighty five workers were recruited, 1,001 in welding trades (447 women), and 884 in electrical trades (438 women). One thousand four hundred and nineteen (75.3%) completed a “wrap up” questionnaire, with 1,413 answering questions on harassment. Sixty percent of women and 32% of men reported that they had been harassed. Those who reported harassment had more frequently recorded episodes of anxiety and depression made worse by work in prospective data. In Alberta, 1,242 were successfully matched to administrative health records. Those who reported harassment were more likely to have a physician record of depression since starting their trade.

Conclusions

Tradeswomen were much more likely than tradesmen to recall incidents of harassment. The results from record linkage, and from prospectively collected reports of anxiety and depression made worse by work, support a conclusion that harassment resulted in poorer mental health.
Specialized metabolites degradation by microorganisms
Authors: Kumano Takuto
Published: January 2024

Secondary metabolites are specialized metabolic products synthesized by plants, insects, and bacteria, some of which exhibit significant physiological activities against other organisms. Plants containing bioactive secondary metabolites have been used in traditional medicine for centuries. In developed countries, one-fourth of medicines directly contain plant-derived compounds or indirectly contain them via semi-synthesis. These compounds have contributed considerably to the development of not only medicine but also molecular biology. Moreover, the biosynthesis of these physiologically active secondary metabolites has attracted substantial interest and has been extensively studied. However, in many cases, the degradation mechanisms of these secondary metabolites remain unclear. In this review, some unique microbial degradation pathways for lignans and C-glycosides are explored.
O10 Multifocal congenital haemangiomas: expanding our understanding of “neonatal haemangiomatosis” – case series
Authors: Peeva Daniela , Petrof Gabriela , Solman Lea
Published: January 2024

Background

Congenital haemangiomas are benign vascular tumours, typically solitary, categorised by their postnatal behaviour as rapidly involuting, non-involuting, or partially involuting. Histologically, they differ from infantile haemangiomas by the lack of immunostaining for GLUT-1. We present three infants with congenital, small, multifocal, non-progressive haemangiomas on the skin.

Cases

Our first patient was a male, born with 18 small vascular lesions. Abdominal ultrasound showed three vascular lesions in his liver and one in his left kidney, which were not visible on the repeated ultrasound in 3 months. MRI of the thorax showed a vascular lesion in the right hemithorax. He was completely asymptomatic, and the lung lesion was monitored annually with ultrasound.

The second patient was a male, born with eight vascular lesions. He had an abdominal ultrasound, which was clear. He was also asymptomatic, and the lesions disappeared in the first year.

The third patient was a female, born with 24 vascular lesions. Cranial ultrasound was clear; however, MRI head revealed nine punctate white matter lesions suggestive of vascular lesions. She had three small foci in the liver, consistent with haemangiomas, which were not detected after 6 weeks.

All three patients had skin biopsy, which showed thin-walled dilated vessels in the dermis, negative for GLUT1 and D240. None of the patients had coagulopathy.

Conclusion

These three cases expand the diagnosis of congenital haemangioma to include a multifocal phenotype and demonstrate their possible association with visceral and intracranial lesions/abnormalities.
P03 EB or not EB? A report of two neonates with congenital blisters
Authors: Bageta Maria , Miller Catherine , Sivakumar Branavan , Balboa Pablo Lopez , Dodein Razan , Petrof Gabriela , Martinez Anna E
Published: January 2024

Neonatal compartment syndrome (NCS) is extremely rare, with less than 100 cases reported. The affected limb usually presents with significant swelling and sentinel skin changes such as desquamation, blisters and skin necrosis. Risk factors that predispose infants to a hypercoagulable state or trauma have been implicated, but the exact cause remains elusive. We report two neonates with no family history of note, except for oligohydramnios in patient 1, who presented with congenital bullae over the upper extremity which led to an open wound. They were both referred to our service with a provisional diagnosis of epidermolysis bullosa (EB). Patient 1 also presented with a reduction in spontaneous movements of the hand shortly after birth.

The wound took weeks to heal with scaring and subcutaneous tissue and muscle loss resulting in significant ulnar deviation by age 9 weeks. This was managed with stretching exercises, splints and surgical intervention. Despite this there remained noticeable limb length discrepancy and functional limitations to date. Patient 2 had a lack range of motion and restricted passive motion on the affected limb by the age of 4 weeks. Subsequent neurophysiological studies showed evidence of a severe chronic median and ulnar neuropathy with distal axonal loss and a right radial neuropathy at the site of the scar.

Clinically, both cases were in keeping with NCS. A skin biopsy and molecular analysis ruled out EB. NCS requires early recognition and intervention as it can lead to long-term sequelae including Volkmann contracture, limb length discrepancies and permanent nerve damage.
P20 A Rare Case of Hereditary Mucoepithelial Dysplasia With Long Term Follow Up
Authors: Vetsiou Evangelia , Hayes Emily , Holden Simon , Burrows Nigel
Published: January 2024

This 28-year old woman initially presented at 2 years of age with patchy alopecia, perianal erythema and widespread rough skin. Prior to her first birthday she was diagnosed with bilateral corneal ulceration and was treated initially with soft contact lenses. She had no features of ichthyosis or hyperkeratosis and teeth, nails and eyelashes were normal. The hair loss progressed with involvement of the eyebrows. On examination, there was widespread keratosis pilaris, perianal and vulval erythema and angular cheilitis. Light microscopy of the cut hair was essentially normal. A clinical diagnosis of hereditary mucoepithelial dysplasia was made at that time. She recently underwent genetic testing which has confirmed the diagnosis. She is now registered blind and wears a wig. Her IQ is normal.

Hereditary mucoepithelial dysplasia (HMD; OMIM 158310) is a rare autosomal dominant genodermatosis characterised by chronic mucosal lesions associated with keratitis, non-scarring alopecia, keratosis pilaris and psoriasiform perineal intertrigo. A novel causative heterozygous pathogenic variant c.1580G>T (p.Arg527Leu) was identified in our patient in the sterol regulatory element-binding factor 1 (SREBF1) gene. This is involved in promoting the transcription of lipogenes that are associated with epidermal cholesterol and fatty acid biosynthesis.

HMD is allelic with autosomal dominant IFAP showing considerable phenotypic overlap and should be considered in patient with congenital hypotrichosis.
P21 Bi-allelic TUFT1 variants in two siblings with woolly hair and skin fragility
Authors: Balboa Pablo Lopez , Bageta Maria L , McGrath John A , Petrof Gabriela , Martinez Anna E
Published: January 2024

TUFT1 encodes tuftelin-1, a glycoprotein thought to play a major role in mineralization and structural organization of enamel, but it has not been implicated in any monogenic enamel disorders.

Recently, Jackson et al. (2023) identified that tuftelin-1 has a role in desmosomal function. Pathology in desmosomal components causes disorders affecting the skin, hair, and heart. Newly described bi-allelic loss-of-function TUFT1 variants (OMIM600087) cause a novel skin fragility-woolly hair phenotype.

We present two siblings from non-consanguineous parents of Irish and British ancestry. Both had normal skin at birth and developed widespread blisters on day two of life, on the limbs, buttocks area and inside the mouth.

Although their skin fragility had improved with age, they still developed flare-ups with multiple small blisters, mainly on their limbs when viral illness. They had mild palmoplantar keratoderma and skin peeling.

Their most characteristic phenotype was slow-­growing woolly hair that did not need cutting until the age of 5 years old in the older sibling. The eyebrows and eyelashes were unaffected. Recently, the older sibling has developed keratosis pilaris on her arms. The heart was unaffected with normal electrocardiogram and echocardiogram. Whole exome sequencing identified homozygous NM_020127:c.60+1G>A TUFT1 variants in both affected individuals.

These two cases reflect a novel condition. The predominant clinical phenotype is woolly hair and early signs of skin fragility. Despite having a role in desmosomal integrity bi-­allelic loss-of-function TUFT1 variants do not appear to cause cardiac pathology.
P23 Successful Control of Systemic Mastocytosis Symptoms in a Two-Year-Old with Omalizumab
Authors: Ramwani Miteshkumar , Kotsapas Constantinos , Clark Sheila , Bartram Jack , Solman Lea
Published: January 2024

A 6-month-old boy presented to us with diffuse cutaneous mastocytosis, experiencing constant severe pruritus, blistering, urticaria, flushing, diarrhoea, and frequent anaphylaxis episodes. He was found to have hepatosplenomegaly and mast cells in the bone marrow aspirate, confirming systemic mastocytosis. His tryptase was significantly elevated (87 ug/ml). A c-KIT D816V mutation was identified in exon 17 through a skin biopsy and peripheral blood testing.

The patient received concomitant treatment with cetirizine (eightfold dosage), hydroxyzine,

chlorphenamine, cimetidine, ketotifen, sodium cromoglicate, and montelukast in addition to topical treatment. Despite the treatment, he continued to have frequent episodes of flushing, anaphylaxis, blisters, and severe pruritus. He required oral prednisolone on several occasions, which provided little relief.

Treatment with Imatinib was not an option, as patients with mastocytosis who have the c-KIT D816V mutation do not respond to it. Due to his poor quality of life, we initiated monthly injections of omalizumab (150 mg sc). After three doses, his DLQI score decreased from 29/30 to 10/30. He had no further anaphylactic episodes, and he had significant reduction in the episodes of flushing, urticaria and blistering. Unfortunately, there was little improvement in his pruritus, which remains troublesome for him, particularly at night. He had no significant side effects of omalizumab.

Conclusion Omalizumab may provide safe and effective management of symptoms in paediatric patients with systemic mastocytosis, refractory to high-dose conventional therapy, particularly in patients who cannot receive imatinib.
P27 Successful treatment of severe eczema and plane warts with Dupilumab in a child with Dedicator of Cytokinesis 8 (DOCK8) deficiency (Autosomal recessive form of hyper-IgE syndrome)
Authors: Oyedepo Jadesola , Worth Austen , Solman Lea
Published: January 2024

A six-year-old girl first presented with severe eczema at the age of 6 months, which was difficult to control with topical treatments. She was found to have severely elevated total IgE and multiple food allergies. Due to recurrent ear and chest infections, and persistent varicella zoster, she was screened for a primary immunodeficiency and found to have a homozygous exon 29-46 deletion in the DOCK8 gene. Her eczema remained challenging, with coalescing warts on her limbs. She started Methotrexate with an initial good response; however, the frequency of infections and hospitalizations increased. After the diagnosis of DOCK8 deficiency was confirmed, she started Dupilumab, resulting in the complete resolution of her eczema and warts. She is awaiting haematopoietic stem cell transplant (HSCT) .

DOCK8 deficiency is an autosomal recessive hyper-IgE syndrome that presents early in life with severe eczema, skin abscesses, multiple food allergies, recurrent respiratory tract infections, and severe viral (including skin) infections. Older patients invariably develop bronchiectasis and are at high risk of malignancy. Patients have a combined immunodeficiency, with T-cell lymphopenia, reduced thymic output and T-cell skewing to a Th2 response. Children with this condition often present to dermatologists because of severe eczema, which is usually difficult to treat with standard topical treatments. The decision to treat with systemic immunosuppression is often challenging due to recurrent infections. Although HSCT is the curative treatment for DOCK8 deficiency, Dupilumab can be used to reduce inflammation and infections, and improve quality of life in patients awaiting HSCT.
P29 Erosive and vesicular dermatitis
Authors: Stavrou Christiana , Leech Suzy
Published: January 2024

We present a case of a 3 year old girl, born at term via normal vaginal delivery, with significant erosive lesions present from birth. Finger and toenails were small and she was systemically well. At day three, there was already evidence of healing and by week two, the erosions had almost fully healed with residual scaling. Once fully resolved, areas of hypopigmented, reticulate scarring remained.

Investigations included swabs for bacterial, fungal and viral infections were negative. There was no concern regarding perinatal infection and apart from oligohydramnios, there were no other issues in pregnancy. She was managed on the burns unit with nutritional support, antibiotics, emollients and dressings.

She subsequently developed a left micro-ophthalmia and cataract, right severe myopia and a mild developmental delay with microcephaly. Older siblings aged 7 and 5 had a history of mild developmental delay and microcephaly. Parents had no relevant medical issues and were both of Jewish background.

Genetic testing was carried out which did not identify a genetic cause with normal microarrays of her siblings.

A diagnosis of vesicular and pustular dermatosis was made, a rare condition, first described in 1985 by Cohen et al. Lesions typically consist of erythema, erosions, crusting, vesicles and fissures which start to heal within 10 days with residual reticulate scarring. Most cases occur in premature infants, making our case less typical. Nail, ophthalmological abnormalities and developmental delay are other associations, seen in our case.
P32 Bullous Pemphigoid in Childhood and Infancy. A case of a 4-months old post vaccination
Authors: Hassanin Sondos , Katira Arnav , Hardcastle Nicola
Published: January 2024

The first case of bullous pemphigoid was reported in 1970, however, this remains a mystery. Two peaks of incidences of BP in childhood have been reported in the first year of life (infantile BP) and around the age of 8 years old. Bullous pemphigoid is characterized by circulating autoantibodies that attack basal skin membrane antigens.

Increasing numbers of cases have recently increased the suspicion around the link to immunization. We present the case of a 4-month-old male born at full term with no family history of skin diseases and progressive blistering disease manifesting as a papulovesicular eruption on the face, acral sites, and the trunk while sparing the back, who also recently received a 12-week vaccination.

He was treated with Steroids, Intravenous immunoglobulin, and Erythromycin. However, management has been challenging due to limited evidence regarding treatment. He responded well with no relapse.

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CD1a and skin T cells: a pathway for therapeutic intervention
Authors: Ye John H , Chen Yi-Ling , Ogg Graham
Published: January 2024

The CD1 and MR1 protein families present lipid antigens and small molecules to T cells, complementing well-studied major histocompatibility complex–peptide mechanisms. The CD1a subtype is highly and continuously expressed within the skin, most notably on Langerhans cells, and has been demonstrated to present self and foreign lipids to T cells, highlighting its cutaneous sentinel role. Alteration of CD1a-dependent T-cell responses has recently been discovered to contribute to the pathogenesis of several inflammatory skin diseases. In this review, we overview the structure and role of CD1a and outline the current evidence implicating CD1a in the development of psoriasis, atopic dermatitis and allergic contact dermatitis.
Transgressive segregation, hopeful monsters, and phenotypic selection drove rapid genetic gains and breakthroughs in predictive breeding for quantitative resistance to Macrophomina in strawberry
Authors: Knapp Steven J , Cole Glenn S , Pincot Dominique D A , Dilla-Ermita Christine Jade , Bjornson Marta , Famula Randi A , Gordon Thomas R , Harshman Julia M , Henry Peter M , Feldmann Mitchell J
Published: January 2024

Two decades have passed since the strawberry (Fragaria x ananassa) disease caused by Macrophomina phaseolina, a necrotrophic soilborne fungal pathogen, began surfacing in California, Florida, and elsewhere. This disease has since become one of the most common causes of plant death and yield losses in strawberry. The Macrophomina problem emerged and expanded in the wake of the global phase-out of soil fumigation with methyl bromide and appears to have been aggravated by an increase in climate change-associated abiotic stresses. Here we show that sources of resistance to this pathogen are rare in gene banks and that the favorable alleles they carry are phenotypically unobvious. The latter were exposed by transgressive segregation and selection in populations phenotyped for resistance to Macrophomina under heat and drought stress. The genetic gains were immediate and dramatic. The frequency of highly resistant individuals increased from 1% in selection cycle 0 to 74% in selection cycle 2. Using GWAS and survival analysis, we found that phenotypic selection had increased the frequencies of favorable alleles among 10 loci associated with resistance and that favorable alleles had to be accumulated among four or more of these loci for an individual to acquire resistance. An unexpectedly straightforward solution to the Macrophomina disease resistance breeding problem emerged from our studies, which showed that highly resistant cultivars can be developed by genomic selection per se or marker-assisted stacking of favorable alleles among a comparatively small number of large-effect loci.
RtNAC055 promotes drought tolerance via a stomatal closure pathway linked to methyl jasmonate/hydrogen peroxide signaling in Reaumuria trigyna
Authors: Ma Binjie , Zhang Jie , Guo Shuyu , Xie Xinlei , Yan Lang , Chen Huijing , Zhang Hongyi , Bu Xiangqi , Zheng Linlin , Wang Yingchun
Published: January 2024

The stomata regulate CO2 uptake and efficient water usage, thereby promoting drought stress tolerance. NAC proteins (NAM, ATAF1/2, and CUC2) participate in plant reactions following drought stress, but the molecular mechanisms underlying NAC-mediated regulation of stomatal movement are unclear. In this study, a novel NAC gene from Reaumuria trigyna, RtNAC055, was found to enhance drought tolerance via a stomatal closure pathway. It was regulated by RtMYC2 and integrated with jasmonic acid signaling and was predominantly expressed in stomata and root. The suppression of RtNAC055 could improve jasmonic acid and H2O2 production and increase the drought tolerance of transgenic R. trigyna callus. Ectopic expression of RtNAC055 in the Arabidopsis atnac055 mutant rescued its drought-sensitive phenotype by decreasing stomatal aperture. Under drought stress, overexpression of RtNAC055 in poplar promoted ROS (H2O2) accumulation in stomata, which accelerated stomatal closure and maintained a high photosynthetic rate. Drought upregulated the expression of PtRbohD/F, PtP5CS2, and PtDREB1.1, as well as antioxidant enzyme activities in heterologous expression poplars. RtNAC055 promoted H2O2 production in guard cells by directly binding to the promoter of RtRbohE, thus regulating stomatal closure. The stress-related genes RtDREB1.1/P5CS1 were directly regulated by RtNAC055. These results indicate that RtNAC055 regulates stomatal closure by maintaining the balance between the antioxidant system and H2O2 level, reducing the transpiration rate and water loss, and improving photosynthetic efficiency and drought resistance.
Global Nonlinear Stability of Traveling Wave Solution to Time-Like Extremal Hypersurface in Minkowski Space
Authors: Liu Jianli , Zhou Yi
Published: January 2024

There are a few results about the global nonlinear stability of nontrivial large solution to quasilinear wave equations. Time-like extremal surface in Minkowski space is an important model of quasilinear wave equation. There are two folds in this paper. Firstly, we get the existence of traveling wave solution to the time-like extremal hypersurface in $\mathbb {R}^{1+(n+1)}$, which can be considered as the generalized Bernstein theorem. For $n=2$, we are also concerned with global stability of traveling wave solutions with speed of light to time-like extremal hypersurface equation in $1+(2+1)$ dimensional Minkowski space, which is corresponding with quasilinear wave equation in two space dimensions.
Protected Beliefs Under the Equality Act: Grainger Questioned
Authors: Patten Keith
Published: January 2024

The definition of what is a ‘protected belief’ for the purpose of the Equality Act 2010 is of significant practical importance. This is because it determines whether people have the right not to be discriminated against and, correspondingly, whether others have the obligation not to discriminate. As such it determines how people can act. Despite this the statute itself offers little assistance in relation to this definition, instead preferring to leave the matter to tribunals to develop. This article looks at the way in which that definition has developed and at the practical difficulties this may give tribunals (both at first instance and on appeal) in deciding whether a particular belief falls to be protected or not.
Tafenoquine-Atovaquone Combination Achieves Radical Cure and Confers Sterile Immunity in Experimental Models of Human Babesiosis
Authors: Vydyam Pratap , Pal Anasuya C , Renard Isaline , Chand Meenal , Kumari Vandana , Gennaro Joseph C , Mamoun Choukri Ben
Published: January 2024

Human babesiosis is a potentially fatal tick-borne disease caused by intraerythrocytic Babesia parasites. The emergence of resistance to recommended therapies highlights the need for new and more effective treatments. Here we demonstrate that the 8-aminoquinoline antimalarial drug tafenoquine inhibits the growth of different Babesia species in vitro, is highly effective against Babesia microti and Babesia duncani in mice and protects animals from lethal infection caused by atovaquone-sensitive and -resistant B. duncani strains. We further show that a combination of tafenoquine and atovaquone achieves cure with no recrudescence in both models of human babesiosis. Interestingly, elimination of B. duncani infection in animals following drug treatment also confers immunity to subsequent challenge. Altogether, the data demonstrate superior efficacy of tafenoquine plus atovaquone combination over current therapies for the treatment of human babesiosis and highlight its potential in providing protective immunity against Babesia following parasite clearance.
Association of piperacillin/tazobactam MIC and mortality in a cohort of ceftriaxone-resistant Escherichia coli bloodstream infections treated with piperacillin/tazobactam and carbapenems: a multicentric propensity score-weighted observational cohort study
Authors: Rando Emanuele , Salvati Federica , Sangiorgi Flavio , Catania Francesca , Leone Elisa , Oliva Alessandra , Di Gennaro Francesco , Fiori Barbara , Cancelli Francesca , Figliomeni Sara , Bobbio Francesca , Sacco Federica , Bavaro Davide Fiore , Diella Lucia , Belati Alessandra , Saracino Annalisa , Mastroianni Claudio Maria , Fantoni Massimo , Murri Rita
Published: January 2024

Objectives

To assess the impact of piperacillin/tazobactam MICs on in-hospital 30 day mortality in patients with third-generation cephalosporin-resistant Escherichia coli bloodstream infection treated with piperacillin/tazobactam, compared with those treated with carbapenems.

Methods

A multicentre retrospective cohort study was conducted in three large academic hospitals in Italy between 2018 and 2022. The study population comprised patients with monomicrobial third-generation cephalosporin-resistant E. coli bloodstream infection, who received either piperacillin/tazobactam or carbapenem therapy within 48 h of blood culture collection. The primary outcome was in-hospital 30 day all-cause mortality. A propensity score was used to estimate the likelihood of receiving empirical piperacillin/tazobactam treatment. Cox regression models were performed to ascertain risk factors independently associated with in-hospital 30 day mortality.

Results

Of the 412 consecutive patients included in the study, 51% received empirical therapy with piperacillin/tazobactam, while 49% received carbapenem therapy. In the propensity-adjusted multiple Cox model, the Pitt bacteraemia score [HR 1.38 (95% CI, 0.85–2.16)] and piperacillin/tazobactam MICs of 8 mg/L [HR 2.35 (95% CI, 1.35–3.95)] and ≥16 mg/L [HR 3.69 (95% CI, 1.86–6.91)] were significantly associated with increased in-hospital 30 day mortality, while the empirical use of piperacillin/tazobactam was not found to predict in-hospital 30 day mortality [HR 1.38 (95% CI, 0.85–2.16)].

Conclusions

Piperacillin/tazobactam use might not be associated with increased mortality in treating third-generation cephalosporin-resistant E. coli bloodstream infections when the MIC is <8 mg/L.
P17 Hepatobiliary parasitic infestation: a case report
Authors: Al-Anee Omar , Bagwan Izhar , Gamage Amila
Published: January 2024

Background

Hepatic parasitic lesions can present with multiple cystic lesions that may simulate inflammatory pseudo-tumour or malignancy in appropriate clinical settings. Here we present a known case of renal cell carcinoma with liver lesions that showed parasitic infestation on histology.

Patient case

A 70-year-old male with a history of right partial nephrectomy for clear cell renal cell carcinoma having an uneventful postoperative follow-up for 2 years underwent a surveillance CT scan. Multiple hepatic cystic lesions were identified, which on subsequent MRI and PET scan were suspicious for metastasis. Partial hepatectomy was performed for histological evaluation.

Results

Multiple discrete cystic hepatic lesions were noted on macroscopy. Histological examination revealed multiple necrotic hyalinized nodules with granulomatous inflammation within the liver and dense neutrophil infiltration with microabscess formation. Within the central necrotic area, there were non-viable parasite eggs and parts of worm, in keeping with parasitic infestation. On further expert opinion, this was diagnosed as Enterobius infestation of liver.

Conclusions

Hepatobiliary parasitic infestations may be encountered as clinically and biochemically asymptomatic lesions, especially in immunocompromised patients. Strong clinical history of travel and parasite serology screen is always helpful to clinch the diagnosis but may not be always available during histological examination. This case highlights the importance of thorough histological and microbiological examination as all nodular lesions in liver are not malignant and could be infective.
P21 A Phase 3 randomized, double-blind, active comparator-controlled study to evaluate the safety, tolerability and immunogenicity of a 21-valent PCV, V116, in pneumococcal vaccine-naive adults (STRIDE-3)
Authors: Bruno Christopher , Buntinx Erik , Pelayo Enrique , Kamerbeek Jackie M , Garcia-Huidobro Diego , Barranco-Santana Elizabeth A , Sjoberg Folke , Song Joon Young , Greenberg David , Grijalva Carlos G , Orenstein Walter A , Morgan Leslie , Fernsler Doreen , Xu Weifeng , Waleed Muhammad , Li Jianing , Buchwald Ulrike K , Platt Heather L
Published: January 2024

Background

Pneumococcal disease (PD) prevention remains an unmet medical need in adults. V116 is an investigational pneumococcal conjugate vaccine (PCV) containing the most prevalent serotypes associated with PD in adults in regions with established paediatric vaccination programmes. This Phase 3 study evaluated safety, tolerability, and immunogenicity of V116 compared with PCV20 in adults.

Methods

Pneumococcal vaccine-naive adults ≥18 years were eligible. Cohort 1 (≥50 years, n=2362) was stratified by age (50–64, 65–74, 75–84 and ≥85) and randomized 1:1 to receive 1 dose of V116 or PCV20, and cohort 2 (18–49 years, n=301) was randomized 2:1 to receive 1 dose of V116 or PCV20. Pneumococcal serotype-specific opsonophagocytic activity (OPA) and IgG responses were measured at baseline (Day 1) and 30 days post vaccination (Day 30). Primary objectives included assessment of (i) non-inferiority of immune responses for the serotypes common to V116 and PCV20 in cohort 1; (ii) superiority of serotypes unique to V116 compared with PCV20 in cohort 1; and (iii) immunobridging from adults 18–49 to adults 50–64 for all 21 serotypes in V116. Safety was evaluated by the proportion of participants with adverse events (AEs).

Results

V116 is non-inferior to PCV20 for the 10 serotypes common to both vaccines as measured by serotype-specific OPA geometric mean titres (GMTs) at Day 30. V116 is superior to PCV20 for 10 of 11 unique serotypes as measured by OPA GMTs at Day 30 as well as based on the proportions of participants with a ≥4-fold rise in OPA from Day 1 to Day 30. V116 elicits comparable immune responses in participants 18–49 years compared with participants 50–64 years for the 21 serotypes in V116 as assessed by serotype-specific OPA GMTs at Day 30, successfully demonstrating immunobridging. In total, 61.7% and 67.2% of participants vaccinated with V116 and PCV20, respectively, had ≥1 AE. There were no vaccine-related serious AEs or vaccine-related deaths.

Conclusions

V116 elicits immune responses that are non-inferior to PCV20 for the common serotypes and superior to PCV20 for 10 of 11 unique serotypes in V116 and has a safety profile comparable to PCV20. This pivotal study supports V116 as a novel population-specific vaccine for the prevention of PD in adults.
P28 Evaluation of one in-house and three commercial phenotypic tests for detection of KPC, NDM and OXA-48-like carbapenemase in Klebsiella pneumoniae: is routine detection possible?
Authors: AlRujaibi Arwa , Rizvi Meher , Al Jabri Zaaima
Published: January 2024

Background

Phenotypic characterization of the OXA-48-like carbapenemase XDR and pandrug-resistant (PDR) Klebsiella pneumoniae in clinical isolates is essential for making informed empirical decisions and critical for strengthening antimicrobial stewardship programmes. This study focused on assessing one in-house and three commercial phenotypic tests for detection of KPC, NDM and OXA-48-like carbapenemases in an attempt to study the feasibility of making detection of OXA-48-like carbapenemases a routine activity of a diagnostic microbiology laboratory.

Methods

A total of 40 representative non-duplicate XDR and PDR clinical Klebsiella pneumoniae isolates were screened on the basis of susceptibility profile, resistance to piperacillin/tazobactam; susceptible, intermediate, or resistant to third generation cephalosporins; elevated MIC for meropenem. These isolates were then subjected to one in-house test (OXA-48 disc test) and three commercial tests: Xpert® Carba-R (Cepheid), MASTDISCS® Combi Carba Plus (D73C), Immunochromatographic assay (ICT); KPC/IMP/NDM/OXA-48 Combo test (LFIA), Medomics.

Results

Xpert ®Carba-R identified OXA-48 in 62.5% (n=25) isolates, NDM in 17.5% (n=7), KPC+NDM co-carriage in 15% (n=6) and KPC in one isolate. Both Xpert® Carba-R and ICT were considered as possible gold standards and the outcomes of the other tests were compared with these two. With Xpert® Carba-R as the gold standard, high sensitivity of 96.15% was detected in OXA-48-like isolates, followed by NDM (92.85%) and NDM+KPC (85.7%). The lowest sensitivity was seen with the OXA-48 disc test (48% in OXA-48, 53.8% in NDM) followed by D73C test (64% in OXA-48, 38.46% in NDM). These two tests could not detect co- carriage of NDM and KPC in six isolates, although in two cases one of the two was detected. Specificity was high among all the tests (96.29%–93.33%). With ICT as the gold standard, 100% sensitivity was reported for NDM and KPC isolates, followed by OXA-48 and KPC+NDM (96% and 83.33%, respectively). The specificity was higher with ICT (99%) than Xpert® Carba-R (96.29%) as in detection of co- carriage of NDM and KPC. In terms of cost ICT ($16 per test) was much cheaper than Xpert® Carba-R($52 per test).

Conclusions

We recommend immunochromatographic assay (ICT) as an excellent tool for detection of carbapenemases (KPC/IMP/NDM/OXA-48). OXA-48 disc test and MASTDISCS® Combi Carba plus (D73C) cannot be considered as good standard since they could not detect co-carriage of NDM and KPC and had lower sensitivity.
P29 Treatment outcomes with rezafungin and caspofungin in people aged 65 years and above with candidaemia and/or invasive candidiasis: integrated analysis of pooled Phase 2 and Phase 3 data
Authors: Cornely Oliver A , Thompson George R , Soriano Alex , Kullberg Bart-Jan , Kollef Marin , Vazquez Jose , Honore Patrick M , Bassetti Matteo , Pullman John , Dignani Cecilia , Das Anita F , Sandison Taylor , Pappas Peter G
Published: January 2024

Background

Factors including frailty and multimorbidity can affect candidaemia and/or invasive candidiasis (C/IC) treatment in older people.1 The current analysis explored data from C/IC patients aged ≥65 years who were treated with rezafungin or caspofungin in the STRIVE (Phase 2: NCT02734862) and ReSTORE (Phase 3: NCT03667690) clinical trials.2,3

Methods

STRIVE and ReSTORE were double-blind, randomized studies. Adults with C/IC, diagnosed by systemic signs and mycological confirmation, received rezafungin once-weekly (Week 1: 400 mg; Weeks 2–4: 200 mg) or once-daily caspofungin (Day 1: 70 mg; Days 2–28: 50 mg) by IV injection for ≥14 days (≤4 weeks). Post hoc analysis examined pooled STRIVE/ReSTORE data for subjects aged ≥65 years. Safety outcomes included treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) in subjects who received ≥1 dose of study drug (safety population). Day 30 all-cause mortality (ACM) and mycological response at Days 5 and 14 were examined for the modified intention-to-treat (mITT) population (subjects with mycological C/IC diagnosis within 96 h of randomization who received ≥1 study drug dose).

Results

The safety population included 132 subjects (rezafungin arm: 64; caspofungin arm: 68). The mITT population included 120 subjects (rezafungin arm: 57; caspofungin arm: 63). The most common TEAEs with rezafungin were hypokalaemia, diarrhoea, vomiting and anaemia (Table 1). Eight subjects reported rezafungin-related TEAEs and seven had caspofungin-related TEAEs. SAEs comprised one case each of first degree atrioventricular block (rezafungin arm) and acute liver injury (caspofungin arm). Day 30 ACM rate was 14.0% (rezafungin arm) and 31.7% (caspofungin arm). The between-group difference (95% CI) was -17.6 (−32.5, −2.8). Day 5 mycological response was 78.9% (rezafungin arm) and 58.7% (caspofungin arm; difference [95% CI]: 19.3 [3.3, 35.2]; Figure 1).

Conclusions

Integrated analysis of pooled STRIVE/ReSTORE study data revealed similar incidence of drug-related TEAEs and SAEs in patients aged ≥65 years treated with rezafungin or caspofungin. Further analyses are required to understand underlying factors influencing between-group differences regarding treatment outcomes.
Practical Considerations for Oncogenic Fusion Detection and Reporting in Solid Tumors
Authors: Solomon James P
Published: January 2024

Background

Chromosomal rearrangements that result in oncogenic fusions can hold tremendous clinical significance in solid tumors, often with diagnostic or treatment implications.

Content

Traditionally, low-throughput methods such as fluorescence in situ hybridization were used to identify fusions in the clinical laboratory. With the rise of next-generation sequencing techniques and the broad adoption of comprehensive genomic profiling, the practice of screening for fusions as part of an oncologic workup has evolved. RNA sequencing methods are increasingly used, as these comprehensive high-throughput assays have many advantages over traditional techniques. Several RNA sequencing platforms are available, each with benefits and drawbacks. Regardless of the approach, systematic evaluation of the RNA sequencing results and the fusions identified by the assay should be performed. Assessment of fusion events relies upon evaluation of quality evidence, structural evidence, and functional evidence to ensure accurate fusion reporting and interpretation.

Given the clinical significance of gene fusions in oncology, understanding the variety of assays available for fusion detection, their benefits and drawbacks, and how they are used in the identification and interpretation of gene fusions is important for the modern precision oncology practice.
FRAX predicts cardiovascular risk in women undergoing osteoporosis screening: the Manitoba bone mineral density registry
Authors: Ye Carrie , Schousboe John T , Morin Suzanne N , Lix Lisa M , McCloskey Eugene V , Johansson Helena , Harvey Nicholas C , Kanis John A , Leslie William D
Published: January 2024

Osteoporosis and cardiovascular disease (CVD) are highly prevalent in older women, with increasing evidence for shared risk factors and pathogenesis. Although FRAX was developed for the assessment of fracture risk, we hypothesized that it might also provide information on CVD risk. To test the ability of the FRAX tool and FRAX-defined risk factors to predict incident CVD in women undergoing osteoporosis screening with DXA, we performed a retrospective prognostic cohort study which included women aged 50 yr or older with a baseline DXA scan in the Manitoba Bone Mineral Density Registry between March 31, 1999 and March 31, 2018. FRAX scores for major osteoporotic fracture (MOF) were calculated on all participants. Incident MOF and major adverse CV events (MACE; hospitalized acute myocardial infarction [AMI], hospitalized non-hemorrhagic cerebrovascular disease [CVA], or all-cause death) were ascertained from linkage to population-based healthcare data.

The study population comprised 59 696 women (mean age 65.7 ± 9.4 yr). Over mean 8.7 yr of observation, 6021 (10.1%) had MOF, 12 277 women (20.6%) had MACE, 2274 (3.8%) had AMI, 2061 (3.5%) had CVA, and 10 253 (17.2%) died. MACE rates per 1000 person-years by FRAX risk categories low (10-yr predicted MOF <10%), moderate (10%–19.9%) and high (≥20%) were 13.5, 34.0, and 64.6, respectively. Although weaker than the association with incident MOF, increasing FRAX quintile was associated with increasing risk for MACE (all P-trend <.001), even after excluding prior CVD and adjusting for age. HR for MACE per SD increase in FRAX was 1.99 (95%CI, 1.96–2.02). All FRAX-defined risk factors (except parental hip fracture and lower BMI) were independently associated with higher non-death CV events.

Although FRAX is intended for fracture risk prediction, it has predictive value for cardiovascular risk.
Bone remodeling and responsiveness to mechanical stimuli in individuals with type 1 diabetes mellitus
Authors: Walle Matthias , Duseja Ankita , Whittier Danielle E , Vilaca Tatiane , Paggiosi Margaret , Eastell Richard , Müller Ralph , Collins Caitlyn J
Published: January 2024

Type 1 diabetes mellitus (T1DM) has been linked to increased osteocyte apoptosis, local accumulation of mineralized lacunar spaces, and microdamage suggesting an impairment of the mechanoregulation network in affected individuals. Diabetic neuropathy might exacerbate this dysfunction through direct effects on bone turnover, and indirect effects on balance, muscle strength, and gait. However, the in vivo effects of impaired bone mechanoregulation on bone remodeling in humans remain underexplored. This longitudinal cohort study assessed consenting participants with T1DM and varying degree of distal symmetric sensorimotor polyneuropathy (T1DM, n = 20, median age 46.5 yr, eight female) and controls (CTRL; n = 9, median age 59.0 yr, four female) at baseline and 4–yr follow-up. Nerve conduction in participants with T1DM was tested using DPNCheck and bone remodeling was quantified with longitudinal high–resolution peripheral quantitative–computed tomography (HR-pQCT, 82 μm) at the standard distal sites. Local trabecular bone formation (Tb.F) and resorption (Tb.R) sites were captured by implementing 3D rigid image registration of HR-pQCT images, and the mechanical environment across the bone microarchitecture at these sites was simulated using micro–finite element analysis. We calculated odds ratios to determine the likelihood of bone formation (ORF) and resorption (ORR) with increasing/decreasing strain in percent as markers for mechanoregulation. At the distal radius, Tb.F was 47% lower and Tb.R was 59% lower in T1DM participants compared with CTRL (P < .05). Tb.F correlated positively with nerve conduction amplitude (R = 0.69, P < .05) in participants with T1DM and negatively with glycated hemoglobin (HbA1c) (R = −0.45, P < .05). Additionally, ORF was 34% lower and ORR was 18% lower in T1DM compared with CTRL (P < .05). Our findings represent in vivo evidence suggesting that bone remodeling in individuals with T1DM is in a state of low responsiveness to mechanical stimuli, resulting in impaired bone formation and resorption rates; these correlate to the degree of neuropathy and level of diabetes control.
Fracture discrimination capability of ulnar flexural rigidity measured via Cortical Bone Mechanics Technology: study protocol for The STRONGER Study
Authors: Warden Stuart J , Dick Andrew , Simon Janet E , Manini Todd M , Russ David W , Lyssikatos Charalampos , Clark Leatha A , Clark Brian C
Published: January 2024

Osteoporosis is characterized by low bone mass and structural deterioration of bone tissue, which leads to bone fragility (ie, weakness) and an increased risk for fracture. The current standard for assessing bone health and diagnosing osteoporosis is DXA, which quantifies areal BMD, typically at the hip and spine. However, DXA-derived BMD assesses only one component of bone health and is notably limited in evaluating the bone strength, a critical factor in fracture resistance. Although multifrequency vibration analysis can quickly and painlessly assay bone strength, there has been limited success in advancing a device of this nature. Recent progress has resulted in the development of Cortical Bone Mechanics Technology (CBMT), which conducts a dynamic 3-point bending test to assess the flexural rigidity (EI) of ulnar cortical bone. Data indicate that ulnar EI accurately estimates ulnar whole bone strength and provides unique and independent information about cortical bone compared to DXA-derived BMD. Consequently, CBMT has the potential to address a critical unmet need: Better identification of patients with diminished bone strength who are at high risk of experiencing a fragility fracture. However, the clinical utility of CBMT-derived EI has not yet been demonstrated. We have designed a clinical study to assess the accuracy of CBMT-derived ulnar EI in discriminating post-menopausal women who have suffered a fragility fracture from those who have not. These data will be compared to DXA-derived peripheral and central measures of BMD obtained from the same subjects. In this article, we describe the study protocol for this multi-center fracture discrimination study (The STRONGER Study).
Fitness consequences of intraguild predation between Spodoptera frugiperda (Lepidoptera: Noctuidae) and Ostrinia furnacalis (Lepidoptera: Crambidae)
Authors: Sripontan Yuwatida , Wanthathaen Chatchaton , Chiu Chun-I
Published: January 2024

The introduction of the fall armyworm, Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae), into Thailand has significantly altered the dynamics of maize pests. It has overshadowed Ostrinia furnacalis (Guenée) (Asian corn borer) (Lepidoptera: Crambidae), previously the most severe maize insect in Thailand. This transition is postulated to stem from the superior intraguild predation (IGP) capabilities of S. frugiperda. To validate this supposition, we assessed the co-distribution patterns and damage locales of both pests within maize fields and analyzed the IGP’s repercussions on their larval growth, survival, and fecundity. Our findings demonstrate that: (i) incidence of O. furnacalis in maize fields is markedly reduced following the introduction of S. frugiperda; (ii) abundance of S. frugiperda and O. furnacalis is negatively correlated in field; (iii) interspecific interactions affect the spatial distributions of S. frugiperda and O. furnacalis on shared plants; (iv) S. frugiperda has lower generation time and higher fecundity; and (v) IGP amplifies the growth rate of S. frugiperda and elevates mortality in O. furnacalis. Moreover, in response to the competitive pressure exerted by S. frugiperda, O. furnacalis exhibited expedited molting and growth without a commensurate increase in size. Our data suggest IGP proficiency underpins S. frugiperda’s dominance in Thai maize fields. We propose a niche differentiation on spatiotemporal distribution facilitating the coexistence of S. frugiperda and O. furnacalis. The impact of S. frugiperda on pest management strategies is discussed.