•Haematological malignancy or anti-CD20 therapies predispose to persistent SARS-CoV-2 infection.•Persistent SARS-CoV-2 infection can facilitate rapid intra-host viral evolution.•Such viral evolution ...gives rise to mutations described in variants of concern.•Synthetic antibody therapy, possibly in combination with antivirals may lead to clearance in certain patients.•(Rapid) viral elimination is associated with resolution of chronic symptoms, so early recognition and treatment is key.
Most patients with SARS-CoV-2 are non-infectious within 2 weeks, though viral RNA may remain detectable for weeks. However there are reports of persistent SARS-CoV-2 infection, with viable virus and ongoing infectivity months after initial detection. Beyond individuals, viral evolution during persistent infections may be accelerated, driving emergence of mutations associated with viral variants of concern. These patients often do not meet inclusion criteria for clinical trials, meaning clinical and virologic characteristics, and optimal management strategies are poorly evidence-based.
We analysed cases of SARS-CoV-2 infection from a regional testing laboratory in South-West England between March 2020 and December 2021, with at least two SARS-CoV-2 positive samples separated by ≥ 56 days were identified. Excluding those with confirmed or likely re-infection, we identified patients with persistent infection, characterised by an ongoing clinical syndrome consistent with COVID-19 alongside monophyletic viral lineage of SARS-CoV-2. We examined clinical and virologic characteristics, treatment, and outcome. We further performed a literature review investigating cases of persistent SARS-CoV-2 infection, reviewing patient characteristics and treatment.
We identified six patients with persistent SARS-CoV-2 infection. All were hypogammaglobulinaemic and had underlying haematological malignancy, with four having received B-cell depleting therapy. Evidence of viral evolution, including accrual of mutations associated with variants of concern, was demonstrated in five cases. Four patients ultimately cleared SARS-CoV-2. In two patients, clearance followed treatment with casirivimab/imdevimab. Both survived beyond thirty days following viral clearance, having experienced infections of 305- and 269-days duration respectively, after failed attempts at clearance with alternative therapies. We found 60 cases of confirmed persistent infection in the literature, with a further 31 probable cases. Of those, 80% of patients treated with monoclonal antibodies cleared SARS-CoV-2, and none died.
Haematological malignancy and patients receiving B-cell depleting therapies represent key groups at risk of persistent SARS-CoV-2 infection. Throughout persistent infection, SARS-CoV-2 can evolve rapidly, giving rise to significant mutations, including those implicated in variants of concern. Monoclonal antibodies appear to be a promising therapeutic option, potentially in combination with antivirals, crucial for individuals, and for public health.
Antibiotics are prescribed for over 50% of respiratory tract infections in primary care, despite good evidence of there being no benefit to the patient, and evidence of over prescribing driving ...microbial resistance. The high treatment rates are attributed to uncertainty regarding microbiological cause and clinical prognosis. Point-of-care-tests have been proposed as potential antibiotic stewardship tools, with some providing microbiological results in 15 minutes. However, there is little research on their impact on antibiotic use and clinical outcomes in primary care.
This is a multi-centre, individually randomised controlled trial with mixed-methods investigation of microbial, behavioural and antibiotic mechanisms on outcomes in patients aged 12 months and over presenting to primary care in the UK with a suspected respiratory tract infection, where the clinician and/or patient thinks antibiotic treatment may be, or is, necessary. Once consented, all participants are asked to provide a combined nose and throat swab sample and randomised to have a rapid microbiological point-of-care-test or no point-of-care-test. For intervention patients, clinicians review the result of the test, before contacting the patient to finalise treatment. Treatment decisions are made as per usual care in control group patients. The primary outcome is whether an antibiotic is prescribed at this point. All swab samples are sent to the central laboratory for further testing. Patients are asked to complete a diary to record the severity and duration of symptoms until resolution or day 28, and questionnaires at 2 months about their beliefs and intention to consult for similar future illnesses. Primary care medical records are also reviewed at 6-months to collect further infection consultations, antibiotic prescribing and hospital admissions. The trial aims to recruit 514 patients to achieve 90% power with 5% significance to detect a 15% absolute reduction in antibiotic prescribing. Qualitative interviews are being conducted with approximately 20 clinicians and 30 participants to understand any changes in beliefs and behaviour resulting from the point-of-care-test and generate attributes for clinician and patient discrete choice experiments.
This trial will provide evidence of efficacy, acceptability and mechanisms of action of a rapid microbiological point-of-care test on antibiotic prescribing and patient symptoms in primary care.
ISRCTN16039192, prospectively registered on 08/11/2022.
Objective. The objective of this study was to examine outcomes in dogs with cruciate ligament rupture (CR) that had chronic radiographic cranial tibial subluxation at the time of osteotomy healing ...after tibial plateau leveling osteotomy (TPLO). Study Design. Retrospective case analysis of 12 dogs with prospective follow-up. Four of the 12 dogs were prospectively studied 12-24 months after surgery to assess long-term radiographic and clinical outcomes. Results. Three of the 4 dogs showed improvement in radiographic cranial tibial subluxation at long-term follow-up. In the other dog, minimally improved cranial tibial subluxation was associated with severe lameness. At long-term follow-up, gait analysis in 3 dogs with improved subluxation showed the symmetry of weight-bearing within 10% for peak vertical force, and no clinically lameness. Preoperative tibial plateau angle (TPA) and radiographic osteoarthritis in dogs with prospective follow-up and all dogs treated with TPLO surgery in the study period were not significantly different. Conclusion. Dogs with chronic radiographic cranial tibial subluxation are acceptable candidates for TPLO. Radiographic improvement in stifle reduction may take more than 10 weeks. The dog with long-term persistent subluxation also had a higher TPA over time, suggestive of ineffective surgical correction with TPLO and treatment failure.
The association between upper respiratory tract microbial positivity and illness prognosis in children is unclear. This impedes clinical decision-making and means the utility of upper respiratory ...tract microbial point-of-care tests remains unknown. We investigated for relationships between pharyngeal microbes and symptom severity in children with suspected respiratory tract infection (RTI).
Baseline characteristics and pharyngeal swabs were collected from 2,296 children presenting to 58 general practices in Bristol, UK with acute cough and suspected RTI between 2011-2013. Post-consultation, parents recorded the severity of six RTI symptoms on a 0-6 scale daily for ≤28 days. We used multivariable hurdle regression, adjusting for clinical characteristics, antibiotics and other microbes, to investigate associations between respiratory microbes and mean symptom severity on days 2-4 post-presentation.
Overall, 1,317 (57%) children with complete baseline, microbiological and symptom data were included. Baseline characteristics were similar in included participants and those lacking microbiological data. At least one virus was detected in 869 (66%) children, and at least one bacterium in 783 (60%). Compared to children with no virus detected (mean symptom severity score 1.52), adjusted mean symptom severity was 0.26 points higher in those testing positive for at least one virus (95% CI 0.15 to 0.38, p<0.001); and was also higher in those with detected Influenza B (0.44, 0.15 to 0.72, p = 0.003); RSV (0.41, 0.20 to 0.60, p<0.001); and Influenza A (0.25, -0.01 to 0.51, p = 0.059). Children positive for Enterovirus had a lower adjusted mean symptom severity (-0.24, -0.43 to -0.05, p = 0.013). Children with detected Bordetella pertussis (0.40, 0.00 to 0.79, p = 0.049) and those with detected Moraxella catarrhalis (-0.76, -1.06 to -0.45, p<0.001) respectively had higher and lower mean symptom severity compared to children without these bacteria.
There is a potential role for upper respiratory tract microbiological point-of-care tests in determining the prognosis of childhood RTIs.
Objective. The objective was to study clinical outcomes in dogs with chronic cruciate ligament rupture (CR) treated with palliative arthroscopy as the sole surgical treatment. Methods. Thirteen ...client-owned dogs with CR underwent physical examination, stifle radiography, and arthroscopy with resection of damaged meniscal tissue. Records were evaluated, and orthopaedic examination, radiographs, and arthroscopy images were assessed. Long-term clinical outcome was also assessed by use of an owner questionnaire. Results. Thirteen dogs that underwent arthroscopy at the UW Veterinary Care between 2001 and 2020 were included. Long-term follow-up was available for 7 of 13 dogs. Lameness was static to improved in all dogs in which arthroscopy was performed. Subsequent stifle stabilization was performed after arthroscopy in only 1 of 7 dogs with follow-up data. Conclusion. Palliative arthroscopy and resection of damaged meniscal tissue in combination with medical management of osteoarthritis can be considered in dogs with chronic CR and cranial tibial subluxation with little passive laxity during examination. Revision surgery with TPLO is uncommon after arthroscopy based on this study.
Here, we report the use of genome-wide association study (GWAS) for the analysis of canine whole-genome sequencing (WGS) repository data using breed phenotypes. Single-nucleotide polymorphisms (SNPs) ...were called from WGS data from 648 dogs that included 119 breeds from the Dog10K Genomes Project. Next, we assigned breed phenotypes for hip dysplasia (Orthopedic Foundation for Animals (OFA) HD,
= 230 dogs from 27 breeds; hospital HD,
= 279 dogs from 38 breeds), elbow dysplasia (ED,
= 230 dogs from 27 breeds), and anterior cruciate ligament rupture (ACL rupture,
= 279 dogs from 38 breeds), the three most important canine spontaneous complex orthopedic diseases. Substantial morbidity is common with these diseases. Previous within- and between-breed GWAS for HD, ED, and ACL rupture using array SNPs have identified disease-associated loci. Individual disease phenotypes are lacking in repository data. There is a critical knowledge gap regarding the optimal approach to undertake categorical GWAS without individual phenotypes. We considered four GWAS approaches: a classical linear mixed model, a haplotype-based model, a binary case-control model, and a weighted least squares model using SNP average allelic frequency. We found that categorical GWAS was able to validate HD candidate loci. Additionally, we discovered novel candidate loci and genes for all three diseases, including
(HD),
,
(ED),
(ED & ACL rupture), and
,
,
,
, and
(ACL rupture). Therefore, categorical GWAS of ancestral dog populations may contribute to the understanding of any disease for which breed epidemiological risk data are available, including diseases for which GWAS has not been performed and candidate loci remain elusive.
Resistance to antibiotics is rising and threatens future antibiotic effectiveness. 'Antibiotic targeting' ensures patients who may benefit from antibiotics receive them, while being safely withheld ...from those who may not. Point-of-care tests may assist with antibiotic targeting by allowing primary care clinicians to establish if symptomatic patients have a viral, bacterial, combined, or no infection. However, because organisms can be harmlessly carried, it is important to know if the presence of the virus/bacteria is related to the illness for which the patient is being assessed. One way to do this is to look for associations with more severe/prolonged symptoms and test results. Previous research to answer this question for acute respiratory tract infections has given conflicting results with studies has not having enough participants to provide statistical confidence.
To undertake a synthesis of IPD from both randomised controlled trials (RCTs) and observational cohort studies of respiratory tract infections (RTI) in order to investigate the prognostic value of microbiological data in addition to, or instead of, clinical symptoms and signs.
A systematic search of Cochrane Central Register of Controlled Trials, Ovid Medline and Ovid Embase will be carried out for studies of acute respiratory infection in primary care settings. The outcomes of interest are duration of disease, severity of disease, repeated consultation with new/worsening illness and complications requiring hospitalisation. Authors of eligible studies will be contacted to provide anonymised individual participant data. The data will be harmonised and aggregated. Multilevel regression analysis will be conducted to determine key outcome measures for different potential pathogens and whether these offer any additional information on prognosis beyond clinical symptoms and signs.
PROSPERO Registration number: CRD42023376769.
Implant failure is common in small animal orthopedics, but risk factors are rarely reported. Our objective was to determine whether abnormal fracture healing was associated with implant failure after ...fracture fixation in dogs and cats in a consecutive series of cases. Thirty-seven client-owned animals (thirty-two dogs, five cats) diagnosed with implant failure after fracture treatment from January 2013-September 2018 were studied. Medical and radiographic records were retrospectively reviewed to identify patients that underwent fracture fixation using open reduction and internal fixation with subsequent radiographic evidence of implant failure. Area moment of inertia (AMI), plate working length, and bone screw density were determined. Implant failure was found in 39 fractures in 37 animals, representing 23% of fracture cases during the study period. Cases of implant failure were at increased risk of delayed union, malunion, or non-union (
< 0.0001). The most common cause of implant failure was loosening (54%); the second most common was plate failure that included low AMI locking plates (28%). Major complications found in 22/39 fractures (56%) were associated with delayed union (
< 0.01). Surgical revision was performed in 49% of implant failure cases. Complications were most frequently identified after treatment of humeral fractures (26%). We conclude mechanical failure of implants increases the risk for delayed or abnormal fracture healing and often requires revision surgery. Implant AMI should be considered during preoperative planning. Locking plates are associated with implant failure if plate bending stiffness is not sufficient, based on findings from this case series.
Anterior cruciate ligament (ACL) rupture is a common condition that can be devastating and life changing, particularly in young adults. A non-contact mechanism is typical. Second ACL ruptures through ...rupture of the contralateral ACL or rupture of a graft repair is also common. Risk of rupture is increased in females. ACL rupture is also common in dogs. Disease prevalence exceeds 5% in several dog breeds, ~100 fold higher than human beings. We provide insight into the genetic etiology of ACL rupture by genome-wide association study (GWAS) in a high-risk breed using 98 case and 139 control Labrador Retrievers. We identified 129 single nucleotide polymorphisms (SNPs) within 99 risk loci. Associated loci (P<5E-04) explained approximately half of phenotypic variance in the ACL rupture trait. Two of these loci were located in uncharacterized or non-coding regions of the genome. A chromosome 24 locus containing nine genes with diverse functions met genome-wide significance (P = 3.63E-0.6). GWAS pathways were enriched for c-type lectins, a gene set that includes aggrecan, a gene set encoding antimicrobial proteins, and a gene set encoding membrane transport proteins with a variety of physiological functions. Genotypic risk estimated for each dog based on the risk contributed by each GWAS locus showed clear separation of ACL rupture cases and controls. Power analysis of the GWAS data set estimated that ~172 loci explain the genetic contribution to ACL rupture in the Labrador Retriever. Heritability was estimated at 0.48. We conclude ACL rupture is a moderately heritable highly polygenic complex trait. Our results implicate c-type lectin pathways in ACL homeostasis.
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