RSS 1.0Laboratory Medicine
Recent Submissions
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Microscopic changes in the multifidus muscle in people with low back pain associated with lumbar disc herniation.Lumbar disc herniation (LDH) is a common degenerative condition causing low back pain (LBP) due to nerve compression. Previous studies show conflicting findings regarding the multifidus (MF) muscle's microscopic changes in LDH patients. So, this study aimed to compare the affected MF to the adjacent MF on the ipsilateral and contralateral sides in LDH patients and examined correlations with clinical features of LBP. Four muscle biopsies were collected from each of 30 surgical participants. Immunohistochemistry was performed on tissue sections and imaged with an epifluorescence microscope. Data was analysed using a two-way ANOVA for muscle fibre cross-sectional area, perimeter, diameter, and composition, while pathological fibres were analysed using a one-way ANOVA. Pearson's correlation was employed to examine MF microscopy associations with clinical features. Results revealed no significant differences between the affected MF and MF from other sites, though significantly more pathological fibres were present in the affected MF (p < 0.05). A weak but significant negative correlation was found between type I fibres and LBP clinical features, though no such correlations were observed for type IIA fibres. In conclusion, LDH primarily impacts the pathological status of the MF rather than fibre phenotype or size, and severity of clinical features is associated with the size of type I fibres.
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The effect of smoking on Sjögren's disease development and severity: a comprehensive literature review.Unlike other autoimmune diseases, little is known about the environmental risk factors for Sjögren's disease (SjD). Smoking is an important risk factor for rheumatoid arthritis but the relationship between smoking and SjD is more complex to understand. Current smoking seems to be negatively linked to SjD, whereas there is mixed data on past smoking. Smoking also seems to impact SjD outcomes, influencing comorbidities like hypertension or associated immune-mediated diseases, and, less clearly, extraglandular involvement, particularly pulmonary disease. Minor salivary gland biopsy findings indicate a lower frequency of positivity associated with smoking, with a potential dose-response relationship. However, smoking's uncertain effect on dryness symptoms complicates interpretation of data with reverse causation remaining a possibility. This review underscores the complexity of the smoking-SjD connection, raising questions about causality and potential protective effects on either SjD's development and/or classification criteria. Understanding these nuances may help unravel SjD pathogenesis and inform future therapeutic strategies.
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Are ultrasound salivary parenchymal lesions more severe in primary Sjögren patients with a longer disease duration? A cross-sectional study.Objectives: Salivary gland ultrasound (SGUS) has an interest in primary Sjögren's disease (pSD) for diagnosis, but the evolution of parenchymal lesions over time is unknown. The objective of this study was to assess the severity of ultrasound abnormalities in relation to pSD duration from the time of buccal dryness onset. Methods: In this cross-sectional international multicentre study, patients with pSD according to the 2002 or 2016 ACR/EULAR classification criteria were included. Parenchymal abnormalities were classified according to the semiquantitative score as defined by OMERACT. Patients were separated into 4 groups (Group A: < 5 years, Group B: 5-9 years, Group C: 10-20 years, and Group D: > 20 years from the onset of buccal dryness). The association between disease duration groups and SGUS lesions was quantified in terms of odds ratios and 95% confidence intervals. Results: A total of 247 patients were consecutively included between May 2019 and February 2022. Eighty-nine percent of patients had a focus score ≥1/4 mm2, and 85% had positive anti-Ro/SSA. pSD duration was associated with a pathological OMERACT score (score 2 or 3): OR for 5-year duration: 1.23 [95% CI 1.04; 1.47], p= 0.0383). Considering each US item, the only statistical association with pSD duration was found regarding the presence of hyperechoic bands (25% or more): OR for five-year duration 1.18 [95% CI 1.03; 1.36], p= 0.038), independent of an older age. Conclusion: pSD duration was associated with the presence of hyperechoic bands, but not with hypoechoic areas, suggesting a progressive fibro-adipose evolution.
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Safety and efficacy of ianalumab in patients with Sjögren's disease: 52-week results from a randomized, placebo-controlled, phase 2b dose-ranging study.Objective: The objective of this study was to report 52-week safety and efficacy of ianalumab from phase 2b dose-finding study in patients with Sjögren's disease (SjD). Methods: Patients randomly received (1:1:1:1) ianalumab (5, 50, or 300 mg) or placebo subcutaneously every 4 weeks until week 24 (treatment period [TP]1). At week 24, patients on 300 mg were rerandomized to continue 300 mg or receive placebo until week 52 (TP2), patients on placebo were switched to ianalumab 150 mg, and patients on 5 and 50 mg directly entered posttreatment safety follow-up. Patients who discontinued treatment early or completed treatment entered safety follow-up (≥20 weeks). Results: During TP1, 190 patients were randomized (placebo = 49, 5 mg = 47, 50 mg = 47, 300 mg = 47). Of these 190 patients, 90 (47.4 %; 43 continued 300 mg and 47 received placebo) entered TP2, and 81 of 90 (90.0%) completed the study treatment. By week 52, efficacy was sustained in patients who continued 300 mg in TP2 (EULAR Sjögren's Syndrome Disease Activity Index, EULAR Sjögren's Syndrome Patient Reported Index, patient global assessment, and physician global assessment change from week 24: -1.45, -0.46, -4.69, and -6.86, respectively). Stimulated salivary flow rates and autoantibody levels numerically improved in the 300 mg group. Treatment-emergent adverse events were not dose-dependent, except for injection-site reactions. Cases of decreased neutrophil counts (Common Terminology Criteria for Adverse Events v4.03 grade 3 according to laboratory listings) were observed in three patients during the posttreatment follow-up, occurring at 3.5, 5.5, and 3 months, after the last ianalumab administration. None were associated with infection except one incidental finding of asymptomatic cytomegalovirus infection (IgM-positive). Conclusion: In patients with SjD, ianalumab 300 mg demonstrated sustained efficacy through week 52 and a favorable safety profile up to two years of follow-up.
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Contemporary dental pharmacology: evidence-based considerations.No abstract available.
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Longitudinal genomic surveillance of a UK intensive care unit shows a lack of patient colonisation by multi-drug-resistant Gram-negative bacterial pathogens.Vulnerable patients in an intensive care unit (ICU) setting are at high risk of infection from bacteria including gut-colonising Escherichia coli and Klebsiella species. Complex ICU procedures often depend on successful antimicrobial treatment, underscoring the importance of understanding the extent of patient colonisation by multi-drug-resistant organisms (MDROs) in large UK ICUs. Previous work on ICUs globally uncovered high rates of colonisation by transmission of MDROs, but the situation in UK ICUs is less understood. Here, we investigated the diversity and antibiotic resistance gene (ARG) carriage of bacteria present in one of the largest UK ICUs at the Queen Elizabeth Hospital Birmingham (QEHB), focusing primarily on E. coli as both a widespread commensal and a globally disseminated multi-drug-resistant pathogen. Samples were taken during highly restrictive coronavirus disease 2019 (COVID-19) control measures from May to December 2021. Whole-genome and metagenomic sequencing were used to detect and report strain-level colonisation of patients, focusing on E. coli sequence types (STs), their colonisation dynamics and antimicrobial resistance gene carriage. We found a lack of multi-drug resistance (MDR) in the QEHB. Only one carbapenemase-producing organism was isolated, a Citrobacter carrying bla KPC-2. There was no evidence supporting the spread of this strain, and there was little evidence overall of nosocomial acquisition or circulation of colonising E. coli. Whilst 22 different E. coli STs were identified, only 1 strain of the pandemic ST131 lineage was isolated. This ST131 strain was non-MDR and was found to be a clade A strain, associated with low levels of antibiotic resistance. Overall, the QEHB ICU had very low levels of pandemic or MDR strains, a result that may be influenced in part by the strict COVID-19 control measures in place at the time. Employing some of these infection prevention and control measures where reasonable in all ICUs might therefore assist in maintaining low levels of nosocomial MDR.
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Drug utilisation study in hospitalised chronic kidney disease patients, using World Health Organisation prescribing indicators: an observational studyBackground: Chronic kidney disease (CKD) is associated with comorbidities and altered pharmacokinetics, making appropriate prescribing, and monitoring necessary to minimise drug-related problems (DRPs). Therefore, this study aimed to describe the drug-utilisation pattern in hospitalised CKD patients. Methods: An observational study was conducted in hospitalised adult (≥18 years old) CKD patients in the UK using WHO prescribing indicators, from November 2021 to April 2022 in a large teaching hospital in England from admission until discharge. This study used STATA version 16 for analysis. Results: The mean number of drugs per prescription was 11.1(±5), the percentage of encounters resulting in the prescription of an antibiotic was 62%, the percentage of drugs prescribed by generic name was 90%, the percentage of encounters resulting in the prescription of an injection was 94%, and the percentage of drugs prescribed from essential drugs list or formulary was 89%. The most frequent drug group prescribed Alimentary Tract and Metabolism was 22%. Longer hospital stays, admission to a renal ward, and the number of comorbidities were independently associated with polypharmacy. Conclusion: Not all prescribing indicators evaluated in this study were in full compliance with WHO recommendations. Polypharmacy was found in most participants which might require interventions to avoid DRPs. Further research is needed to evaluate factors associated with prescribing in the CKD population and prescriber perspectives on decision-making in the context of available guidelines and patient factors.
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Impact of the timing of immunotherapy administration on overall survival for resectable non-small cell lung cancer (iACORN study): A systematic review and meta-analysis of randomised trialsBackground: We sought to investigate the relative impact of the timing of the administration of immunotherapy on survival in patients with resectable lung cancer. Methods: We conducted a systematic review and meta-analysis of randomised controlled trials in this setting. We searched MEDLINE, EMBASE, LILACS and Cochrane Library databases from 1st January 1980 onwards. We excluded case reports; non-randomised studies; studies without an immunotherapy arm and if there was incomplete reporting on outcome data including conference abstracts. A standardised, pre-piloted form was used to extract data from the included studies for the assessment of study quality and for evidence synthesis. The primary outcome measure was overall survival which was assessed using random-effects meta-analyses (DerSimonian and Laird). The study was registered with PROSPERO (CRD42023407825). Findings: We screened 865 studies and assessed 58 full text articles after removing non-human, non-surgical studies. These studies collectively enrolled 4982 participants and 4425 were included in the respective analyses. Hazard ratios (HRs) for death by timing of administration of immunotherapy, i.e., Neoadjuvant (pre-operative), peri-operative and post-operative were 0.57 (95 % CI 0.302-1.08), 0.67 (95 % CI 0.39-1.13) and 0.94 (95 % CI 0.29-3.06) respectively. The timing of administration accounted for 100 % of the difference in true effect size (test of moderators (QM p = 0.127), residual I2 0 %, p = 0.561). OR for adverse events was higher in the neoadjuvant setting compared to the peri-operative setting; 1.49 (0.64-3.47) and 1.34 (1.08-1.66) respectively. Bias assessment found the majority of studies to be low risk with respect to random sequencing, incomplete outcomes, and selective reporting. Interpretation: In resectable non-small cell lung cancer, administration of adjuvant chemo-immunotherapy regimens in clinical trials did not lead to statistically significant survival benefits. Overall survival outcomes of neoadjuvant and peri-operative chemo-immunotherapy were comparable, but given the shorter duration and lower costs, neoadjuvant chemo-immunotherapy can be considered the current multimodality combination of choice.
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Outcomes of X-linked agammaglobulinaemia patientsBackground: X-linked agammaglobulinaemia (XLA), caused by mutations in BTK, is characterised by low or absent peripheral CD19 + B lymphocytes and agammaglobulinaemia. The mainstay of treatment consists of immunoglobulin replacement therapy (IgRT). As this cannot fully compensate for the immune defects in XLA, patients may therefore continue to be at risk of complications. Objectives: To describe the clinical outcomes of XLA patients in the United Kingdom and Hong Kong and evaluate current treatment strategies. Methods: Patients with a definitive diagnosis of XLA were included in this cross-sectional and retrospective analysis of clinical health outcomes. Data pertaining to diagnosis, infection incidence, IgG trough levels and lung function were collected and analysed. Results: 99 patients with a median age of 29.02 years (IQR 12.83-37.41) and a total follow up of 1922 patient years, were included this study. The median age at diagnosis was 3.30 years (IQR 1.04-8.38) which decreased over time (p = 0.004). 40% of the cohort had radiological evidence of bronchiectasis. Risk of bronchiectasis was not significantly associated with clinical infection incidence (p = 0.880) or IgG trough levels (p = 0.407). Two patients demonstrated novel complications, namely persistent norovirus infection, leading to haemopoietic stem cell transplantation (HSCT). Conclusions: Despite modern therapy, most XLA patients continue to experience complications, most notably bronchiectasis, likely due to absence of IgA/M in current therapies, but lack of B lymphocytes may also lead to additional sequalae. These data strongly support the need for further research, particularly that of curative modalities including HSCT and gene therapy.
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Recommendations for assessing commutability of a replacement batch of a secondary calibrator certified reference materialCommutable secondary certified reference materials (CRMs) play an essential role in the calibration hierarchy of many in-vitro diagnostic measurement procedures used in the medical laboratory. Therefore, sustainable availability of these CRMs is crucial to guarantee the long-term equivalence of results obtained for the clinical samples. The IFCC Working Group on Commutability in Metrological Traceability (WG-CMT) has published several recommendations for assessing the commutability of secondary calibrator CRMs. Performing a full commutability study according to these recommendations may present significant demands on the resources of CRM producers. This report provides recommendations for performing commutability equivalence assessments between existing CRMs of proven commutability and replacement batches of those CRMs. The approach evaluates the relationship of measurement results obtained with the relevant measurement procedures for the replacement batch versus the existing CRM batch. If this relationship is the same, the commutability properties of the replacement batch are considered equivalent to those of the existing CRM batch. Since the existing batch has a suitable commutability, the commutability of the replacement batch is also declared fit for purpose. Because this commutability equivalence assessment involves certain risks, a small number of representative clinical samples are included as safeguards. There are several prerequisites for performing the commutability equivalence assessment and producers of secondary CRMs will probably need to implement improvements before using this approach. However, once the improvements are implemented, the commutability equivalence assessment approach will significantly reduce the resources needed to maintain the supply of CRMs.
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Pre-analytical stability of haematinics, lactate dehydrogenase and phosphate in whole blood at room temperature up to 24 h, and refrigerated serum stability of lactate dehydrogenase, folate and vitamin B12 up to 72 h using the CRESS checklistObjectives: There is a lack of analyte stability data in whole blood (WB). The aim of this study was to determine the allowable delay in WB processing for lactate dehydrogenase (LDH), folate, vitamin B12, iron and phosphate measurement. The stability of LDH, folate and vitamin B12 was also assessed in stored serum at clinically relevant time points. Methods: Blood was taken from n=10 volunteers into Sarstedt serum gel tubes. We assessed stability in WB at room temperature up to 24 h, and stability in refrigerated serum up to 72 h. Mean percentage deviation at each time point was compared to criteria for minimum allowable bias. Results: Results produced from one individual were removed due to discordant results, leaving n=9 specimens at each time point. Stability of folate and phosphate was variable in WB across 24 h, but was deemed to be clinically acceptable. LDH was unstable in WB, iron was stable for at least 12 h, and vitamin B12 and ferritin were acceptable for up to 24 h. Serum LDH, folate and vitamin B12 all demonstrated acceptable stability in refrigerated serum stored for up to 72 h. Conclusions: Blood should ideally be centrifuged within 7 h for phosphate, LDH and folate, and 12 h for iron. However, for phosphate, folate and iron, there is likely to be little clinical impact if serum separation is delayed up to 24 h. Further research is needed to assess LDH stability in WB at 0-12 h, but changes are minimal at 12 h. All other analytes assessed showed acceptable stability across the time-points tested.
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Determinants of HBeAg loss during follow-up of a multiethnic pediatric cohortHepatitis B e antigen (HBeAg) loss is a key event in the natural history of chronic hepatitis B virus infection. The rate and determinants of HBeAg loss depend upon cohort characteristics at baseline. Few studies have examined the age-dependent rate, and none have examined the effect of patient sex and ethnicity on the age-dependant rate. The study of age-dependent rates requires the identification and long-term follow-up of a pediatric cohort. We have studied the age-dependent rate of HBeAg loss, and the rate of HBeAg loss measured from baseline, in a multi-ethnic cohort of 454 pediatric patients. During observation, HBeAg loss was observed in 121/303 (39.9%) HBeAg-positive patients. The rate of HBeAg loss was greater in the second versus the first and third decades of life. The age-related rate of HBeAg loss was clearly affected by patient sex and ethnicity, with earlier loss observed for males and for White versus both South Asian and Chinese ethnicities. When measured from baseline, Chinese patients had a slower rate of HBeAg loss in comparison with White patients. In multivariate analysis of HBeAg loss during prolonged follow-up, male sex, older age, and White ethnicity were associated with HBeAg loss, but antiviral treatment was not.
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Investigation into the linearity of the Roche c 702 carbamazepine assay.Background: Carbamazepine is an anticonvulsant drug which is monitored in patients due to toxic side effects. At Manchester University NHS Foundation Trust (MFT), carbamazepine is measured using Roche's Kinetic Interaction of Microparticles in Solution (KIMS) method on the c 702 platform. The assay has an upper limit of linearity of 20 mg/L. Samples with concentrations above this limit should be identified and manually diluted. However, a poor EQA return from UK NEQAS for Tox and TDM Distribution 456 has highlighted an issue with the Roche KIMS assay. Sample A of the distribution had a carbamazepine concentration of 36 mg/L but was underreported by several Roche users. This indicated that the assay was not consistently identifying high concentration samples which required a dilution. Method: In this investigation, fresh frozen plasma was spiked with carbamazepine concentrations ranging from 15 to 40 mg/L. The spiked samples and EQA material were analysed at two clinical laboratories using the Roche KIMS assay. Results: Samples spiked with concentrations 20-30 mg/L were not consistently identified for dilution by the analyser. This was observed at both hospital sites. Spike samples and EQA with concentrations >30 mg/L were correctly identified at both sites. Conclusion: The manual dilution policy has been changed at MFT, so all samples with a carbamazepine level ≥15 mg/L will be manually diluted. The problem was reported to Roche who are investigating the issue further. We would suggest that other laboratories look at validating their dilution protocols.
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A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel diseasePrecision medicine in immune-mediated inflammatory diseases (IMIDs) requires a cellular understanding of treatment response. We describe a therapeutic atlas for Crohn's disease (CD) and ulcerative colitis (UC) following adalimumab, an anti-tumour necrosis factor (anti-TNF) treatment. We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies (41 subjects), revealing disease-specific differences. A systems biology-spatial analysis identified granuloma signatures in CD and interferon (IFN)-response signatures localising to T cell aggregates and epithelial damage in CD and UC. Pretreatment differences in epithelial and myeloid compartments were associated with remission outcomes in both diseases. Longitudinal comparisons demonstrated disease progression in nonremission: myeloid and T cell perturbations in CD and increased multi-cellular IFN signalling in UC. IFN signalling was also observed in rheumatoid arthritis (RA) synovium with a lymphoid pathotype. Our therapeutic atlas represents the largest cellular census of perturbation with the most common biologic treatment, anti-TNF, across multiple inflammatory diseases.
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Round cells in diagnostic semen analysis: a guide for laboratories and cliniciansRound cells in seminal fluid are defined as either leucocytes or immature germ cells. Laboratories undertaking semen analysis often report these combined as a concentration, with no further review, comment or direction for clinician action or review. Although numerous publications discuss the possible clinical relevance of these cells (particularly leucocytes) in infertility, the methods employed to differentiate them are often beyond the scope of most diagnostic laboratories. This paper aims to support healthcare scientists in understanding the clinical significance of round cells and aid their identification, differentiation and interpretation. This will support the quality of care the patient receives and direct clinicians to further considerations that may be appropriate for their patient and should consequently reduce indiscriminate and unnecessary use of antibiotics.
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Robinow syndrome in an extremely preterm infant: novel homozygous ROR2 variant detected by rapid exome sequencingAn extremely preterm infant presented with clinical and radiological features of Robinow syndrome including butterfly vertebrae, posterior rib fusion, brachydactyly, nail hypoplasia, and retromicrognathia resulting in difficult endotracheal intubation in the intensive care setting. Rapid trio exome sequencing detected a novel homozygous likely pathogenic missense variant in the ROR2 gene, NM_004560.3:c.950A>G, p.(Tyr317Cys), for which both parents were heterozygous carriers. In-silico protein modeling predicted a deleterious effect on the function of the protein. We report an extreme premature infant with novel homozygous likely pathogenic variant in the ROR2 gene consistent with autosomal recessive Robinow syndrome. This case expands the phenotypic and genotypic spectrum of this disorder and highlights the benefit of performing rapid exome sequencing early during evaluation to aid in patient management and providing accurate genetic counseling to families.
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Reverse-transcription loop-mediated isothermal amplification has high accuracy for detecting severe acute respiratory syndrome coronavirus 2 in saliva and nasopharyngeal/oropharyngeal swabs from asymptomatic and symptomatic IndividualsPrevious studies have described reverse-transcription loop-mediated isothermal amplification (RT-LAMP) for the rapid detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in nasopharyngeal/oropharyngeal swab and saliva samples. This multisite clinical evaluation describes the validation of an improved sample preparation method for extraction-free RT-LAMP and reports clinical performance of four RT-LAMP assay formats for SARS-CoV-2 detection. Direct RT-LAMP was performed on 559 swabs and 86,760 saliva samples and RNA RT-LAMP on extracted RNA from 12,619 swabs and 12,521 saliva samples from asymptomatic and symptomatic individuals across health care and community settings. For direct RT-LAMP, overall diagnostic sensitivity (DSe) was 70.35% (95% CI, 63.48%-76.60%) on swabs and 84.62% (95% CI, 79.50%-88.88%) on saliva, with diagnostic specificity of 100% (95% CI, 98.98%-100.00%) on swabs and 100% (95% CI, 99.72%-100.00%) on saliva, compared with quantitative RT-PCR (RT-qPCR); analyzing samples with RT-qPCR ORF1ab CT values of ≤25 and ≤33, DSe values were 100% (95% CI, 96.34%-100%) and 77.78% (95% CI, 70.99%-83.62%) for swabs, and 99.01% (95% CI, 94.61%-99.97%) and 87.61% (95% CI, 82.69%-91.54%) for saliva, respectively. For RNA RT-LAMP, overall DSe and diagnostic specificity were 96.06% (95% CI, 92.88%-98.12%) and 99.99% (95% CI, 99.95%-100%) for swabs, and 80.65% (95% CI, 73.54%-86.54%) and 99.99% (95% CI, 99.95%-100%) for saliva, respectively. These findings demonstrate that RT-LAMP is applicable to a variety of use cases, including frequent, interval-based direct RT-LAMP of saliva from asymptomatic individuals who may otherwise be missed using symptomatic testing alone.