Post-transplant lymphoproliferative disorders following kidney transplantation: A literature review with updates on risk factors, prognostic indices, screening strategies, treatment and analysis of donor type.

Post-transplant lymphoproliferative disorders (PTLD) is a devastating complication of kidney transplantation with an insidious presentation and potential to disseminate aggressively. This review delineates the risk factors, prognostic indexes, screening, current management algorithm and promising treatment strategies for PTLD. Kidneys from both extended criteria donors (ECD) and living donors (LD) are being increasingly used to expand the donor pool. This review also delineates whether PTLD outcomes vary based on these donor sources. While Epstein-Barr virus (EBV) is a well-known risk factor for PTLD development, the use of T-cell depleting induction agents has been increasingly implicated in aggressive, monomorphic forms of PTLD. Research regarding maintenance therapy is sparse. The international prognostic index seems to be the most validate prognostic tool. Screening for PTLD is controversial, as annual PET-CT is most sensitive but costly, while targeted monitoring of EBV-seronegative patients was more economically feasible, is recommended by the American Society of Transplantation, but is limited to a subset of the population. Other screening strategies such as using Immunoglobulin/T-cell receptor require further validation. A risk-stratified approach is taken in the treatment of PTLD. The first step is the reduction of immunosuppressants, after which rituximab and chemotherapy may be introduced if unsuccessful. Some novel treatments have also shown potential benefit in studies: brentuximab vedotin, chimeric antigen receptor T-cell therapy and EBV-specific cytotoxic T lymphocytes. Analysis of LD v DD recipients show no significant difference in incidence and mortality of PTLD but did reveal a shortened time to development of PTLD from transplant. Analysis of SCD vs ECD recipients show a higher incidence of PTLD in the ECD group, which might be attributed to longer time on dialysis for these patients, age, and the pro-inflammatory nature of these organs. However, incidence of PTLD overall is still extremely low. Efforts should be focused on optimising recipients instead. Minimising the use of T-cell depleting therapy while encouraging research on the effect of new immunosuppressants on PTLD, screening for EBV status are essential, while enabling shared decision-making during counselling when choosing kidney donor types and individualised risk tailoring are strongly advocated.

Patient, parent and carer perspectives surrounding expedited paediatric epilepsy surgery.

OBJECTIVE: Most paediatric epilepsies with MRI visible lesions do not respond to antiseizure pharmacotherapy. Such medication resistance, which often takes years to become formally defined, is commonly required for surgical candidacy. Expedited surgical referral at lesional epilepsy diagnosis may result in better seizure, cognitive and developmental prognoses. This study explored the views of patients, parents and carers regarding epilepsy surgery, treatment priorities, and participation in a proposed expedited surgery trial. METHODS: 205 patients, parents and carers (61% UK-based, 26% North American) responded to electronic surveys from February to May 2022. Participants were recruited through social media sites, epilepsy charities and societies. Categorical choice and free-text questions were used to investigate participant perspectives, and Pearson's chi-squared test was utilised to detect meaningful differences amongst respondent subgroups. RESULTS: Almost 90% of respondents who had experienced epilepsy surgery (either themselves or their child) reported seizure cessation or reduction. Postoperative outcome measures prioritised most frequently were seizure freedom (66%), quality of life (47%), seizure severity (30%), seizure frequency (28%) and independence (27%). Most participants support expedited surgery in suitable patients (65%), with just over half (51%) willing to participate in the proposed trial. Many participants (37%) were undecided, often due to fears surrounding neurosurgery. Subgroup perspectives were broadly similar, with more parents and caregivers favouring expedited surgery compared to patients (p = .016) and more UK-based participants willing to take part in an expedited surgery trial compared to those from North America (p = .01). CONCLUSIONS: Patients, parents and carers are open to considering expedited surgery for lesional epilepsies and would support a trial exploring this approach. Priorities from treatment were largely similar between participant subgroups, with seizure, quality of life and neuropsychological outcomes ranked highly. Accounting for these preferences will facilitate the delivery of a trial that is patient- and caregiver-focused, enhancing feasibility, satisfaction and benefit for prospective participants.

Rotational Platform for Real-Time Localization for Active Implantable Medical Devices.

This paper presents a sensor based localization system to localize active implantable medical devices i.e., Wireless Capsule Endoscopy (WCE). The importance of localizing the capsule arises once the images from the capsule detect the abnormalities in the Gastrointestinal tract (GI). A successful system can determine the location that associated with the abnormality for further medical investigation or treatment. The system proposed in this paper comprises a rotational platform that consists of magnetic sensors to detect the position of the embedded magnet in the capsule. The rotational platform provides advantageousness in terms of reducing the number of the sensors and increasing the monitoring accuracy during the real time movement.

Clinician views regarding early surgery for paediatric epilepsy.

OBJECTIVE: Many children with lesional epilepsies progress to drug resistance, a criterion required for surgical referral. Expedited surgery may reduce exposure of the developing brain to uncontrolled seizures, improving cognitive outcomes. Designing a trial comparing early surgery with standard care necessitates input from specialist clinicians regarding feasibility and measurable outcomes, which this study investigated. METHODS: Online surveys were disseminated from June-July 2022 via regional paediatric epilepsy networks and professional societies. 51 UK clinicians responded, mostly paediatricians, paediatric neurologists and epilepsy specialist nurses. Candidacy for epilepsy surgery, outcome measures and support for the proposed study were surveyed. Clinician views were compared by speciality, using Pearson's chi-squared tests to explore differences. RESULTS: 76-98 % of clinicians would refer children for presurgical evaluation at/before drug resistance development across four subgroups (those younger/older than two years, and those with/without a detectable lesion). Earlier referral, at/before epilepsy diagnosis, was considered mostly in those with visible lesions (53 %) and those under two years (31 %). 73 % would consider early surgery before drug resistance is established. Top outcomes to measure were seizure freedom (39 %) and quality of life (22 %). Views of paediatric neurologists and paediatricians did not differ (p > .05). SIGNIFICANCE: Clinician opinions generally aligned with published guidance regarding epilepsy surgery referral. Some remain cautious to refer young children with lesions prior to trialling more than one antiseizure medication. Most support early surgery in appropriate patients, with seizure and quality of life outcomes rated highly. Incorporating these perspectives will aid future trial design, recruitment and clinical utility.

Acute-onset polyradiculoneuropathy after SARS-CoV2 vaccine in the West and North Midlands, United Kingdom.

INTRODUCTION/AIMS: We aimed to determine whether specific severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccines may be associated with acute-onset polyradiculoneuropathy and if they may result in particular clinical presentations. METHODS: We retrospectively reviewed records of all persons presenting with acute-onset polyradiculoneuropathy from January 1, 2021, to June 30, 2021, admitted to two Neuroscience centers, of the West and North Midlands, United Kingdom. We compared subjects with previous SARS-CoV2 vaccine exposure with a local cohort of persons with acute-onset polyradiculoneuropathy admitted between 2005 and 2019 and compared admission numbers for the studied time frame with that of the previous 3 years. RESULTS: Of 24 persons with acute-onset polyradiculoneuropathy, 16 (66.7%) presented within 4 weeks after first SARS-CoV2 vaccine. Fourteen had received the AstraZeneca vaccine and one each, the Pfizer and Moderna vaccines. The final diagnosis was Guillain-Barré syndrome (GBS) in 12 and acute-onset chronic inflammatory demyelinating polyneuropathy in 4. Among AstraZeneca vaccine recipients, facial weakness in nine persons (64.3%), bulbar weakness in seven (50%), and the bifacial weakness and distal paresthesias GBS variant in three (21.4%), were more common than in historical controls (P = .01; P = .004, and P = .002, respectively). A 2.6-fold (95% confidence interval: 1.98-3.51) increase in admissions for acute-onset polyradiculoneuropathy was noted during the studied time frame, compared to the same period in the previous 3 years. DISCUSSION: Despite a low risk, smaller than that of SARS-CoV2 infection and its complications, exposure to the first dose of AstraZeneca SARS-CoV2 vaccine may be a risk factor for acute-onset polyradiculoneuropathy, characterized by more common cranial nerve involvement.

Brainstem encephalitis and acute polyneuropathy associated with hepatitis E infection.

A 59-year-old man presented with feverish illness. His Glasgow Coma Scale was 15, had reduced visual acuity in the left eye with partial left ptosis and mild left hemiparesis with an extensor left plantar. Over 48 hours, he accrued multiple cranial nerves palsies and progressed to a flaccid paralysis necessitating admission to an intensive care unit.Cerebrospinal fluid (CSF) study showed 20 lymphocytes and raised protein. Viral and bacterial PCRs were negative. Samples for Lyme, blood-borne viruses, syphilis and autoantibodies were also negative. MRI brain showed T2 abnormalities within the brainstem. Nerve conduction studies revealed an acute motor and sensory axonal neuropathy pattern of Guillian Barre Syndrome (GBS). The patient was treated for both infective and inflammatory causes of brainstem encephalitis and GBS.Retrospective studies confirmed the presence of hepatitis E virus (HEV) RNA in CSF and serum studies showed positive HEV IgG and IgM prior to intravenous infusion. After 3 months of intensive rehabilitation, the patient was discharged home walking with a frame.

Expression of the murine norovirus (MNV) ORF1 polyprotein is sufficient to induce apoptosis in a virus-free cell model.

Investigations into human norovirus infection, replication and pathogenesis, as well as the development of potential antiviral agents, have been restricted by the lack of a cell culture system for human norovirus. To date, the optimal cell culture surrogate virus model for studying human norovirus biology is the murine norovirus (MNV). In this report we generate a tetracycline-regulated, inducible eukaryotic cell system expressing the entire MNV ORF1 polyprotein. Once induced, the MNV ORF1 polyprotein was faithfully processed to the six mature non-structural proteins that predominately located to a discrete perinuclear region, as has been observed in active MNV infection. Furthermore, we found that expression of the ORF1 polyprotein alone was sufficient to induce apoptosis, characterised by caspase-9 activation and survivin down-regulation. This cell line provides a valuable new tool for studying MNV ORF1 non-structural protein function, screening for potential antiviral agents and acts as a proof-of-principle for such systems to be developed for human noroviruses.

Diagnostic utility of coeliac disease: a descriptive study in a tertiary care hospital, oman.

OBJECTIVES: The prevalence of coeliac disease in Oman is unknown. We aim to estimate the prevalence of coeliac disease in at-risk subjects, describe the clinical characteristics and laboratory findings associated with coeliac disease and the validity of serological testing for coeliac disease at the Royal Hospital, Oman over a period of three years. METHODS: This is a retrospective case finding study. The medical and laboratory records were reviewed for patients for whom serum antiendomysium IgA antibodies were requested at the Royal Hospital during a 3-year period (1(st) Jan 2006-31(st) Dec 2008). The data were extracted in order to assess the following: a) Prevalence rate of coeliac disease among at-risk subjects; b) Clinical characteristics in patients with coeliac disease and clinical manifestations for which the requesting clinicians considered coeliac disease as a possible diagnosis, including their specialties; c) Laboratory tests results in patients with coeliac disease; and d) Validity of antiendomysium antibodies testing in comparison with histopathology of jejunal biopsies for diagnosing coeliac disease. RESULTS: The study included 431 patients (250 females, 181 males) who were suspected of having (or screened for) coeliac disease. The median of age was 15 years (range: 9 months-74 years) with mean ± SD 18.95 ± 14.1 years. Of these, 15 (3.5%) patients (10 females, 5 males) with a median age of 19 years and mean 21.4 ± 13.0 years (range: 2.5-38 years), had positive antiendomysium antibodies results with median (range) of 160 (40-320) IU/L and mean± SD 204.5 ± 160 IU/L. Of these 15 patients, 13 had positive jejunal histopathological changes indicative of coeliac disease; the remaining 2 patients had no biopsy examination. Of the 44 patients with negative antiendomysium antibodies <10 IU/L who had jejunal biopsy, 41 were negative and 3 had histopathological changes suggestive of mild coeliac disease. All the 3 patients had serum total IgA levels within the reference range. The calculated validity indicators for antiendomysium antibodies were: sensitivity 81.3%, specificity 100%, positive predictive value 100%, negative predictive value 93.2% and efficiency 94.7%. The most common mode of presentation in patients with coeliac disease was gastrointestinal features, type 1 diabetes mellitus, anemia, short stature and hypothyroidism. The seropositivity in tye 1 diabetics was 4.9%. Investigations for coeliac disease were most frequently made by endocrinologists (pediatric and adult) who accounted for 53.8% followed by gastroenterologists (pediatric and adult) with 40.6% with less consideration by the other clinicians (5.6%). CONCLUSION: The availability of highly specific and sensitive serological test and increased awareness for coeliac disease among some medical specialties has increased the number of diagnosed cases of coeliac disease. The requesting for serological test is being made mainly by endocrinologists and gastroenterologists.

Infection of calves with bovine norovirus GIII.1 strain Jena virus: an experimental model to study the pathogenesis of norovirus infection.

The experimental infection of newborn calves with bovine norovirus was used as a homologous large animal model to study the pathogenesis of norovirus infection and to determine target cells for viral replication. Six newborn calves were inoculated orally with Jena virus (JV), a bovine norovirus GIII.1 strain, and six calves served as mock-inoculated controls. Following infection, calves were euthanized before the onset of diarrhea (12 h postinoculation [hpi]), shortly after the onset of diarrhea (18 to 21 hpi), and postconvalescence (4 days pi [dpi]). Calves inoculated with JV developed severe watery diarrhea at 14 to 16 hpi, and this symptom lasted for 53.5 to 67.0 h. Intestinal lesions were characterized by severe villus atrophy together with loss and attenuation of villus epithelium. Viral capsid antigen (JV antigen) was detected by immunohistochemistry in the cytoplasm of epithelial cells on villi. In addition, granular material positive for JV antigen was detected in the lamina propria of villi. Lesions first appeared at 12 hpi and were most extensive at 18 to 19 hpi, extending from midjejunum to ileum. The intestinal mucosa had completely recovered at 4 dpi. There was no indication of systemic infection as described for norovirus infection in mice. JV was found in intestinal contents by reverse transcription-PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) as early as 12 hpi. Fecal shedding of the virus started at 13 hpi and stopped at 23 hpi or at necropsy (4 dpi), respectively. Throughout the trial, none of the control calves tested positive for JV by ELISA or RT-PCR.

The Neisseria meningitidis macrophage infectivity potentiator protein induces cross-strain serum bactericidal activity and is a potential serogroup B vaccine candidate.

A gene encoding a 29-kDa protein from Neisseria meningitidis serogroup B strain MC58 with homology to the macrophage infectivity potentiator (MIP) protein of Legionella pneumophila was cloned and expressed in Escherichia coli, and the purified soluble recombinant protein (rMIP) was used for immunization studies. Analysis of the predicted amino acid sequences of MIP from 13 well-characterized meningococcal strains, isolated from carriers or patients and differing in serogroup, serotype, and subtype, showed that the protein was highly conserved (98 to 100%), with only three distinct sequence types (designated I, II, and III) found. Western blotting showed that the MIP protein was expressed at similar levels by all of these strains. Immunization of mice with type I MC58 rMIP in detergent micelles and liposomes containing monophosphoryl lipid A (MPLA) induced high levels of surface-reactive antibodies with serum bactericidal activity (SBA) titers of 1/1,024 against the homologous strain. Bactericidal antibodies were also induced with the protein in saline alone and liposomes alone (titers, 1/128) but not following adsorption to Al(OH)(3). Significantly, antisera raised against type I rMIP administered in saline or liposomes killed strains of heterologous sequence types II and III with similar SBA titers (1/128 to 1/256). Taken together, these findings suggest that rMIP can provide cross-strain protection against meningococci and should be considered a potential antigen for inclusion in new vaccines against meningococcal infection.

Chemical constituents of Osyris alba and their antiparasitic activities.

Phytochemical investigation of Osyris alba L. (Santalaceae) of Jordanian origin resulted in the isolation and identification of one new pyrrolizidine alkaloid, osyrisine (1), together with 16 other known compounds. The structures of all compounds were established on the basis of spectroscopic analysis. Osyrisine, catechin, and catechin-3-O-α-L-rhamnopyranoside exhibited a significant level of antiparasitic activity against two parasites, Entamoeba histolytica and Giardia intestinalis.

Penicillin induced persistence in Chlamydia trachomatis: high quality time lapse video analysis of the developmental cycle.

BACKGROUND: Chlamydia trachomatis is a major human pathogen with a unique obligate intracellular developmental cycle that takes place inside a modified cytoplasmic structure known as an inclusion. Following entry into a cell, the infectious elementary body (EB) differentiates into a non-infectious replicative form known as a reticulate body (RB). RBs divide by binary fission and at the end of the cycle they redifferentiate into EBs. Treatment of C.trachomatis with penicillin prevents maturation of RBs which survive and enlarge to become aberrant RBs within the inclusion in a non-infective persistent state. Persistently infected individuals may be a reservoir for chlamydial infection. The C.trachomatis genome encodes the enzymes for peptidoglycan (PG) biosynthesis but a PG sacculus has never been detected. This coupled to the action of penicillin is known as the chlamydial anomaly. We have applied video microscopy and quantitative DNA assays to the chlamydial developmental cycle to assess the effects of penicillin treatment and establish a framework for investigating penicillin induced chlamydial persistence. PRINCIPAL FINDINGS: Addition of penicillin at the time of cell infection does not prevent uptake and the establishment of an inclusion. EB to RB transition occurs but bacterial cytokinesis is arrested by the second binary fission. RBs continue to enlarge but not divide in the presence of penicillin. The normal developmental cycle can be recovered by the removal of penicillin although the large, aberrant RBs do not revert to the normal smaller size but remain present to the completion of the developmental cycle. Chromosomal and plasmid DNA replication is unaffected by the addition of penicillin but the arrest of bacterial cytokinesis under these conditions results in RBs accumulating multiple copies of the genome. CONCLUSIONS: We have applied video time lapse microscopy to the study of the chlamydial developmental cycle. Linked with accurate measures of genome replication this provides a defined framework to analyse the developmental cycle and to investigate and provide new insights into the effects of antibiotic treatments. Removal of penicillin allows recovery of the normal developmental cycle by 10-20 hrs and the process occurs by budding from aberrant RBs.

Co-evolution of genomes and plasmids within Chlamydia trachomatis and the emergence in Sweden of a new variant strain.

BACKGROUND: Chlamydia trachomatis is the most common cause of sexually transmitted infections globally and the leading cause of preventable blindness in the developing world. There are two biovariants of C. trachomatis: 'trachoma', causing ocular and genital tract infections, and the invasive 'lymphogranuloma venereum' strains. Recently, a new variant of the genital tract C. trachomatis emerged in Sweden. This variant escaped routine diagnostic tests because it carries a plasmid with a deletion. Failure to detect this strain has meant it has spread rapidly across the country provoking a worldwide alert. In addition to being a key diagnostic target, the plasmid has been linked to chlamydial virulence. Analysis of chlamydial plasmids and their cognate chromosomes was undertaken to provide insights into the evolutionary relationship between chromosome and plasmid. This is essential knowledge if the plasmid is to be continued to be relied on as a key diagnostic marker, and for an understanding of the evolution of Chlamydia trachomatis. RESULTS: The genomes of two new C. trachomatis strains were sequenced, together with plasmids from six C. trachomatis isolates, including the new variant strain from Sweden. The plasmid from the new Swedish variant has a 377 bp deletion in the first predicted coding sequence, abolishing the site used for PCR detection, resulting in negative diagnosis. In addition, the variant plasmid has a 44 bp duplication downstream of the deletion. The region containing the second predicted coding sequence is the most highly conserved region of the plasmids investigated. Phylogenetic analysis of the plasmids and chromosomes are fully congruent. Moreover this analysis also shows that ocular and genital strains diverged from a common C. trachomatis progenitor. CONCLUSION: The evolutionary pathways of the chlamydial genome and plasmid imply that inheritance of the plasmid is tightly linked with its cognate chromosome. These data suggest that the plasmid is not a highly mobile genetic element and does not transfer readily between isolates. Comparative analysis of the plasmid sequences has revealed the most conserved regions that should be used to design future plasmid based nucleic acid amplification tests, to avoid diagnostic failures.

Behind the chlamydial cloak: the replication cycle of chlamydiaphage Chp2, revealed.

Studying the replication of the chlamydiaphages presents significant challenges. Their host bacteria, chlamydiae, have a unique obligate intracellular developmental cycle. Using qPCR, immunochemistry, and electron microscopy, the life cycle of chlamydiaphage Chp2 was characterised. Chp2 infection has a dramatic inhibitory effect on bacterial cell division. The RB to EB transition is arrested and RBs enlarge without further division. There is a phase of rapid Chp2 genome replication 36 to 48 h post infection that is coincident with the expression of viral proteins and the replication of the host chromosome. The end stage of Chp2 replication is characterised by the appearance of paracrystalline structures followed by bacterial cell lysis. These data indicate that the Chp2 life cycle is closely coordinated with the developmental cycle of its bacterial host. This is a remarkable adaptation by a microvirus to infect and replicate in a bacterial host that has an obligate intracellular developmental cycle.

Translation termination reinitiation between open reading frame 1 (ORF1) and ORF2 enables capsid expression in a bovine norovirus without the need for production of viral subgenomic RNA.

A generally accepted view of norovirus replication is that capsid expression requires production of a subgenomic transcript, the presence of capsid often being used as a surrogate marker to indicate the occurrence of viral replication. Using a polymerase II-based baculovirus delivery system, we observed capsid expression following introduction of a full-length genogroup 3 norovirus genome into HepG2 cells. However, capsid expression occurred as a result of a novel translation termination/reinitiation event between the nonstructural-protein and capsid open reading frames, a feature that may be unique to genogroup 3 noroviruses.