Repeat testing of mpox specimens with late CTs improves detection of potential false positive cases.

The mpox pandemic necessitated the rapid development of clinical assays for monkeypox virus detection. While the majority of mpox specimens have high viral loads with corresponding early cycle threshold (CT) values, reports have indicated some specimens with late CT values can represent false positive results. To mitigate this risk, the Centers for Disease Control and Prevention (CDC) published an advisory recommending repeat testing of all specimens with CT values ≥34. However, limited experimental data were available to support this specific cutoff. In this study, we examine whether a more conservative approach in which all specimens with CT values ≥29 are repeated would improve the detection of potential false positive results. Compared to the CDC algorithm, our approach identified an additional 20% (5/25) of potential false positive results. To assess the impact of this cutoff on laboratory workload, we modeled the expected increase in test volume and turnaround time (TAT) relative to the CDC method. Using a lower repeat threshold, test volume increased by 0.7% while mean TAT increased by less than 15 minutes. Overall, a lower threshold than recommended by the CDC for repeating late CT mpox specimens may reduce the number of false positives reported while minimally impacting testing volume and TAT.

Pulmonary Co-Infections Detected Premortem Underestimate Postmortem Findings in a COVID-19 Autopsy Case Series.

Bacterial and fungal co-infections are reported complications of coronavirus disease 2019 (COVID-19) in critically ill patients but may go unrecognized premortem due to diagnostic limitations. We compared the premortem with the postmortem detection of pulmonary co-infections in 55 fatal COVID-19 cases from March 2020 to March 2021. The concordance in the premortem versus the postmortem diagnoses and the pathogen identification were evaluated. Premortem pulmonary co-infections were extracted from medical charts while applying standard diagnostic definitions. Postmortem co-infection was defined by compatible lung histopathology with or without the detection of an organism in tissue by bacterial or fungal staining, or polymerase chain reaction (PCR) with broad-range bacterial and fungal primers. Pulmonary co-infection was detected premortem in significantly fewer cases (15/55, 27%) than were detected postmortem (36/55, 65%; p < 0.0001). Among cases in which co-infection was detected postmortem by histopathology, an organism was identified in 27/36 (75%) of cases. Pseudomonas, Enterobacterales, and Staphylococcus aureus were the most frequently identified bacteria both premortem and postmortem. Invasive pulmonary fungal infection was detected in five cases postmortem, but in no cases premortem. According to the univariate analyses, the patients with undiagnosed pulmonary co-infection had significantly shorter hospital (p = 0.0012) and intensive care unit (p = 0.0006) stays and significantly fewer extra-pulmonary infections (p = 0.0021). Bacterial and fungal pulmonary co-infection are under-recognized complications in critically ill patients with COVID-19.

Clinical testing of pediatric mpox specimens: Unique features and challenges in a low prevalence population.

BACKGROUND: Pediatric mpox cases comprise less than 0.3% of the total cases reported in the United States during the global 2022 outbreak. As a result, relatively little is known about the epidemiology or performance characteristics of clinical testing in this group. METHODS: We retrospectively extracted and analyzed results for pediatric mpox specimens tested at a national reference laboratory from July to December 2022. RESULTS: During our study period 13.4% (2,063/15,385) of specimens were from individuals <18 years of age. The positivity rate of pediatric specimens was significantly lower than in adults (1.3% vs 22.3%). The pediatric cohort also consisted of a higher percentage of females (42.7% vs 31.0%) and lower percentage of specimens from genital sources (9.0% vs 19.7%) as compared to adults. In children, specimens were most frequently collected from 1-year-olds (10.1%) and least frequently from 11-year-olds (3.5%). Positivity rates were disproportionately elevated in the less than 1-year-old and 17-year-old age groups (7.8% and 6.4%, respectively). Ct values of positive cases were not statistically different between pediatric and adult cohorts (25.2 vs 22.2, p>0.05). When all pediatric cases with an initial positive mpox result were examined, 5/26 were classified as inconclusive and 2/26 were determined to be false positives. The positive predictive value of monkeypox virus detection was 90.5% (95% CI: 70.4-97.4%) in children. CONCLUSION: These results highlight important differences between pediatric and adult mpox populations and reinforce the need for clinical correlation when reporting positive results from a low prevalence population.

Review of the Clinical Presentation, Pathology, Diagnosis, and Treatment of Leishmaniasis.

Leishmaniasis is a vector-borne infection caused by kinetoplastid protozoans in the genera Leishmania and Endotrypanum. The disease occurs worldwide in the tropics and subtropics and can be particularly burdensome in resource-limited settings. Diseases caused by leishmaniasis range in severity from mild cutaneous lesions to life-threatening visceral and disfiguring mucocutaneous illnesses. Rapid and accurate diagnosis is needed to ensure proper clinical management of patients afflicted with this disease. Complicating matters of diagnosis and treatment are the diversity of species within these 2 genera and the variable specificity of diagnostic assays. This mini-review provides laboratory professionals with an overview of Leishmania epidemiology, biology, pathogenesis, clinical presentations, and treatments with additional emphasis placed on the nuances involved in diagnosis.

Clinical Performance and Trends during the First Two Months of Monkeypox Virus PCR Testing at Two United States Reference Labs.

Recently, a sustained human-to-human outbreak of monkeypox virus (MPXV), a member of the Orthopoxvirus genus, which includes the etiologic agent of smallpox, has been documented in multiple nonendemic countries, including the United States. Prior to June 2022, testing in the United States was limited to public health labs and the Centers for Disease Control and Prevention. Following recognition of the scope of the outbreak, testing for MPXV has expanded into clinical laboratories. Here, we examine epidemiological characteristics, specimen collection practices, and cycle threshold (Ct) values for 10,019 MPXV PCR tests performed at two reference laboratories. Results from both laboratories support public health data showing a high positivity rate in men (>30%) and those ages 30 to 49 (25 to 35%). The overall positivity rate decreased during the study period but remains elevated (~20%). There was a significant difference in Ct values between laboratories (ARUP 23.9 versus UW 25.4) and collection method (22.8 for dry swab versus 24.4 for VTM), likely reflecting slight differences in specimen processing. When multiple specimens were collected for a single individual, the overall result concordance rate was greater than 95%, with less than 1.5% of individuals receiving three or more tests having a single positive result. Compared to the overall positive cohort, individuals with three or more swabs collected and a single positive result had significantly higher Ct values (22.9 versus 35.0). Intriguingly, individuals aged 50 to 59 years old had a significantly different viral load distribution than those found in younger age groups, potentially associated with prior vaccinia virus vaccination. These results provide an early snapshot of testing in the United States during the monkeypox virus outbreak and support restricting the number of swabs collected per individual.

Characterization of the Cytopathic Effects of Monkeypox Virus Isolated from Clinical Specimens and Differentiation from Common Viral Exanthems.

While the practice of viral culture has largely been replaced by nucleic acid amplification tests, circumstances still exist in which the availability of viral culture will allow for the diagnosis of infections not included in a provider's differential diagnosis. Here, we examine the cytopathic effects (CPE) and clinical data associated with 18 cases of monkeypox virus (MPXV) isolated from 19 clinical samples submitted for viral culture. During the study period, a total of 3,468 viral cultures were performed with herpes simplex virus (HSV) most commonly isolated (646/3,468; 18.6%), followed by MPXV (19/3,468; 0.6%) and varicella-zoster virus (VZV) (12/3,468; 0.4%). Most MPXV-positive samples were obtained from males (14/19) and taken from genital (7/19) or rectal lesions (5/19). Cycle threshold values of tested samples ranged from 15.3 to 29.0. Growth of MPXV in cell culture was rapid, yielding detectable CPE at a median of 2 days (range: 1 to 4) often with >50% of the monolayer affected in RMK, BGM, A549, and MRC-5 cell lines. As clinical features of MPXV, HSV, and VZV lesions may overlap, CPE patterns were compared between viruses. HSV CPE developed in a similar time frame (median: 2 days, range: 1 to 7) but was more often negative in RMK cells relative to MPXV. VZV grew more slowly (median: 9 days, range: 5 to 11) and demonstrated CPE affecting ≤25% of cell monolayers when positive. Viral culture remains an important tool for the detection of rare or emerging viral pathogens, particularly when high viral load specimens are easily obtained.

Cokeromyces recurvatus Incidentally Found in a Patient with Gastric Outlet Obstruction.

Isolation of Cokeromyces recurvatus, a dimorphic mucormycete fungus, from clinical specimens poses a diagnostic challenge to physicians and laboratorians as this organism may represent a rare colonizer or true pathogen. Here, we report a case of Cokeromyces recurvatus present in a circumferential duodenal lesion. The patient is a 64-year-old with no past medical history, admitted with a three-week history of left upper quadrant abdominal pain. Computerized tomography scan identified duodenitis with significant gastric outlet obstruction, confirmed by the presence of a partially obstructing non-bleeding duodenal ulcer on upper endoscopy. Histology showed variably sized spherical structures without nuclei, reproductive tracts, or alimentary tracts. Small, clustered spherules representing putative endospores were observed within the larger structures and in the exudate. Based on the histology, the differential included Coccidioides spp, Emmonsia spp, or Chrysosporium spp. Additionally, gastric biopsies revealed concurrent Helicobacter pylori gastritis. The fungus was identified as C. recurvatus by broad-range fungal polymerase chain reaction performed on formalin-fixed paraffin-embedded biopsy tissue, as well as morphology and DNA sequencing of the cultured isolate. The fungus had low MICs to all major antifungal classes; however, in the context of the Helicobacter pylori infection, the patient was only treated with amoxicillin and clarithromycin with improvement in his symptoms before hospital discharge. Only three cases of Cokeromyces recurvatus isolated from the GI tract have been reported; this case highlights a unique clinical presentation in the small bowel in a patient without underlying medical conditions.

Single nucleotide polymorphism rs 2070874 at Interleukin-4 is associated with increased risk of type 1 diabetes mellitus independently of human leukocyte antigens.

INTRODUCTION: Type 1 diabetes mellitus (T1DM) is characterized by autoimmune destruction of insulin-producing pancreatic beta (ß-) cells. Previous studies suggested an imbalance between and pro- and anti-inflammatory cytokines exacerbates T1DM development. OBJECTIVES: We aimed to test the hypothesis that patients with T1DM carry a higher frequency of regulatory genes associated with low levels of the anti-inflammatory cytokines interleukin-4 (IL-4), its receptor (IL-4R), and interleukin-10 (IL-10). METHODS: Accordingly, we compared frequencies of five different single nucleotide polymorphisms (SNPs) in T1DM patients and healthy controls who had been typed for HLA-DRB1, HLA-DQA1, and HLA-DQB1 genes. RESULTS: The frequencies of rs2070874 (IL-4) alleles C and T differed between T1DM patients and controls (cp = 0.0065), as did their codominant (cp = 0.026) and recessive (cp = 0.015) models. Increased frequencies were observed in T1DM patients for HLA alleles: DRB1*03 (pc < 0.0013), DRB1*04 (cp = 0.0169), DQA1*03 (cp = 0.0222), DQA1*05 (cp < 0.0006), DQB1*02 (cp = 0.0005), and DQB1*06 (cp < 0.0005). And lower frequencies were observed for: DRB1*07 (cp = 0.0078), DRB1*11 (cp = 0.0013), DRB1*13 (cp < 0.0364), DRB1*15 (cp < 0.0013), DQA1*01 (cp < 0.0006), and DQA1*02 (cp = 0.0348). Certain DRB1: DQA1: DQB1 haplotypes showed greater frequencies, including, 03:05:02 (p < 0.0001) and 04:03:03 (p = 0.0017), whereas others showed lower frequencies, including, 07:02:02 (p = 0.0032), 11:05:03 (p = 0.0007), and 15:01:06 (p = 0.0002). Stratification for the above HLA haplotypes with rs2070874 C/C exhibited no significant differences between T1DM patients overall and controls. However, when stratified for the vulnerable HLA haplotype (03:05:02/04:03:03), young patients in whom T1DM began at ≤13 years had a higher frequency of the SNP (rs2070874 C/C); a gene associated with low IL-4 production (p < 0.024). CONCLUSION: This study suggests that possession of the rs2070874 C/C genotype, which is associated with low production of IL-4, increases the risk of T1DM in young individuals carrying vulnerable HLA alleles/haplotypes.

Anti-SARS-CoV-2 Antibody Levels Measured by the AdviseDx SARS-CoV-2 Assay Are Concordant with Previously Available Serologic Assays but Are Not Fully Predictive of Sterilizing Immunity.

With the availability of widespread SARS-CoV-2 vaccination, high-throughput quantitative anti-spike protein serological testing will likely become increasingly important. Here, we investigated the performance characteristics of the recently FDA-authorized semiquantitative anti-spike protein AdviseDx SARS-CoV-2 IgG II assay compared to the FDA-authorized anti-nucleocapsid protein Abbott Architect SARS-CoV-2 IgG, Roche Elecsys anti-SARS-CoV-2-S, EuroImmun anti-SARS-CoV-2 enzyme-linked immunosorbent assay (ELISA), and GenScript surrogate virus neutralization assays and examined the humoral response associated with vaccination, natural protection, and vaccine breakthrough infection. The AdviseDx assay had a clinical sensitivity at 14 days after symptom onset or 10 days after PCR detection of 95.6% (65/68; 95% confidence interval [CI], 87.8 to 98.8%), with two discrepant individuals seroconverting shortly thereafter. The AdviseDx assay demonstrated 100% positive percent agreement with the four other assays examined using the same symptom onset or PCR detection cutoffs. Using a recently available WHO international standard for anti-SARS-CoV-2 antibody, we provide assay unit conversion factors to international units for each of the assays examined. We performed a longitudinal survey of healthy vaccinated individuals, finding that median AdviseDx immunoglobulin levels peaked 7 weeks after first vaccine dose at approximately 4,000 IU/ml. Intriguingly, among the five assays examined, there was no significant difference in antigen binding level or neutralizing activity between two seropositive patients protected against SARS-CoV-2 infection in a previously described fishing vessel outbreak and five health care workers who experienced vaccine breakthrough of SARS-CoV-2 infection, all with variants of concern. These findings suggest that protection against SARS-CoV-2 infection cannot currently be predicted exclusively using in vitro antibody assays against wild-type SARS-CoV-2 spike. Further work is required to establish protective correlates for SARS-CoV-2 infection.

IL-13 is a driver of COVID-19 severity.

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here, we report that elevated IL-13 was associated with the need for mechanical ventilation in 2 independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab, a mAb that blocks IL-13 and IL-4 signaling, had less severe disease. In SARS-CoV-2-infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, hyaluronan synthase 1 (Has1) was the most downregulated gene, and accumulation of the hyaluronan (HA) polysaccharide was decreased in the lung. In patients with COVID-19, HA was increased in the lungs and plasma. Blockade of the HA receptor, CD44, reduced mortality in infected mice, supporting the importance of HA as a pathogenic mediator. Finally, HA was directly induced in the lungs of mice by administration of IL-13, indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and HA has important implications for therapy of COVID-19 and, potentially, other pulmonary diseases. IL-13 levels were elevated in patients with severe COVID-19. In a mouse model of the disease, IL-13 neutralization reduced the disease and decreased lung HA deposition. Administration of IL-13-induced HA in the lung. Blockade of the HA receptor CD44 prevented mortality, highlighting a potentially novel mechanism for IL-13-mediated HA synthesis in pulmonary pathology.

Association of single-nucleotide polymorphisms in tumour necrosis factor and human leukocyte antigens genes with type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease characterized by progressive destruction of insulin-producing pancreatic beta cells. This multifactorial disease has a strong genetic component associated with the human leukocyte antigens (HLA) and non-HLA regions. In this study, we compared frequencies of HLA-DRB1 alleles and single-nucleotide polymorphisms (SNPs) associated the genes coding for: toll-like receptors (TLRs), tumour necrosis factor (TNF), interleukin-1 (IL-1), interleukin-1 receptor type 1 (IL-1R1), interleukin-1 receptor antagonist (IL-1RN), interleukin-2 (IL-2) and interleukin-12B (IL-12B), between T1D patients and healthy controls. The aim was to identify frequency differences and linkage between these genetic markers in T1D patients and healthy controls. Twelve SNPs were investigated as follows: rs16944 (IL-1B), rs1143634 (IL-1B), rs1800587 (IL-1A), rs2069762 (IL-2), rs3212227 (IL-12B), rs2234650 (IL-1R1), rs315952 (IL-1RN), rs3804099 (TLR2), rs4986790 (TLR4), rs4986791 (TLR4), rs1800629 (TNF) and rs361525 (TNF). TaqMan genotype assay method was used for SNPs genotyping. HLA-DRB1* genes were typed by Sequence Specific Oligonucleotide Probe (SSOP). SPSS and SNPStats programs were used for the statistical analysis. Significant differences between T1D and control groups were found for the dominant model of rs361525 and rs1800629A:rs361525G genotypes for TNF. Increased frequencies of DRB1*03 and DRB1*04 and decreased frequencies of DRB1*07, DRB1*11 and DRB1*13 and DRB1*15 were observed in T1D patients compared with controls. However, the genotype, DRB1*07 with rs1800629A/G was associated with T1D. We have confirmed that DRB1*03 and DRB1*04 are associated with increased risk and DRB1*07, DRB1*11 and DRB1*13 and DRB1*15 with decreased risk of T1D. Also, the dominant model of rs361525A, and the rs1800629G:361525A genotype were associated with increased risk. The simultaneous presence of DRB1*07 and rs1800629A/G genotypes in 23 out of 27 DRB1*07 positive T1D patients implied that islet cell peptide processing may have been biased towards autoimmunity by upregulation of TNF associated intronic SNPs.

In Vivo Generation of BK and JC Polyomavirus Defective Viral Genomes in Human Urine Samples Associated with Higher Viral Loads.

Defective viral genomes (DVGs) are parasitic viral sequences containing point mutations, deletions, or duplications that might interfere with replication. DVGs are often associated with viral passage at high multiplicities of infection in culture systems but have been increasingly reported in clinical specimens. To date however, only RNA viruses have been shown to contain DVGs in clinical specimens. Here, using direct deep sequencing with multiple library preparation strategies and confirmatory digital droplet PCR (ddPCR) of urine samples taken from immunosuppressed individuals, we show that clinical BK polyomavirus (BKPyV) and JC polyomavirus (JCPyV) strains contain widespread genomic rearrangements across multiple loci that likely interfere with viral replication. BKPyV DVGs were derived from BKPyV genotypes Ia, Ib-1, and Ic. The presence of DVGs was associated with specimens containing higher viral loads but never reached clonality, consistent with a model of parasitized replication. These DVGs persisted during clinical infection as evidenced in two separate pairs of samples containing BK virus collected from the same individual up to 302 days apart. In a separate individual, we observed the generation of DVGs after a 57.5-fold increase in viral load. In summary, by extending the presence of DVGs in clinical specimens to DNA viruses, we demonstrate the ubiquity of DVGs in clinical virology.IMPORTANCE Defective viral genomes (DVGs) can have a significant impact on the production of infectious virus particles. DVGs have only been identified in cultured viruses passaged at high multiplicities of infection and RNA viruses collected from clinical specimens; no DNA virus in the wild has been shown to contain DVGs. Here, we identified BK and JC polyomavirus DVGs in clinical urine specimens and demonstrated that these DVGs are more frequently identified in samples with higher viral loads. The strains containing DVGs had rearrangements throughout their genomes, with the majority affecting genes required for viral replication. Longitudinal analysis showed that these DVGs can persist during an infection but do not reach clonality within the chronically infected host. Our identification of polyomavirus DVGs suggests that these parasitic sequences exist across the many classes of viruses capable of causing human disease.

Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of an ongoing pandemic, with increasing deaths worldwide. To date, documentation of the histopathological features in fatal cases of the disease caused by SARS-CoV-2 (COVID-19) has been scarce due to sparse autopsy performance and incomplete organ sampling. We aimed to provide a clinicopathological report of severe COVID-19 cases by documenting histopathological changes and evidence of SARS-CoV-2 tissue tropism. METHODS: In this case series, patients with a positive antemortem or post-mortem SARS-CoV-2 result were considered eligible for enrolment. Post-mortem examinations were done on 14 people who died with COVID-19 at the King County Medical Examiner's Office (Seattle, WA, USA) and Snohomish County Medical Examiner's Office (Everett, WA, USA) in negative-pressure isolation suites during February and March, 2020. Clinical and laboratory data were reviewed. Tissue examination was done by light microscopy, immunohistochemistry, electron microscopy, and quantitative RT-PCR. FINDINGS: The median age of our cohort was 73·5 years (range 42-84; IQR 67·5-77·25). All patients had clinically significant comorbidities, the most common being hypertension, chronic kidney disease, obstructive sleep apnoea, and metabolic disease including diabetes and obesity. The major pulmonary finding was diffuse alveolar damage in the acute or organising phases, with five patients showing focal pulmonary microthrombi. Coronavirus-like particles were detected in the respiratory system, kidney, and gastrointestinal tract. Lymphocytic myocarditis was observed in one patient with viral RNA detected in the tissue. INTERPRETATION: The primary pathology observed in our cohort was diffuse alveolar damage, with virus located in the pneumocytes and tracheal epithelium. Microthrombi, where observed, were scarce and endotheliitis was not identified. Although other non-pulmonary organs showed susceptibility to infection, their contribution to the pathogenesis of SARS-CoV-2 infection requires further examination. FUNDING: None.

High-resolution profiling of human cytomegalovirus cell-free DNA in human plasma highlights its exceptionally fragmented nature.

Human cytomegalovirus (CMV) infections comprise a leading cause of newborn impairments worldwide and are pervasive concerns among the immunocompromised. Quantification of CMV viral loads is increasingly used to guide definitions of CMV disease but standardization of CMV quantitation remains problematic, mostly due to differences in qPCR amplicon sizes between clinical laboratories. Here, we used plasma cfDNA sequencing data from 2,208 samples sent for non-invasive prenatal aneuploidy screening to detect CMV and precisely measure the length of CMV fragments in human plasma. CMV reads were identified in 120 (5.4%) samples. Median cfDNA fragment size derived from CMV was significantly shorter than cfDNA derived from human chromosomes (103 vs 172 bp, p < 0.0001), corresponding to the 3rd percentile of human cfDNA. Sequencing of cfDNA from seven plasma samples from transplant patients positive for CMV confirmed the extraordinarily short nature of CMV cfDNA fragment size with a median length of 149 bp. We further show that these high-resolution measurements of CMV DNA fragment size accurately predict measured discrepancies in serum viral load measurements by different qPCR assays. These results highlight the exceptionally fragmented nature of CMV cfDNA and illustrate the promise of plasma cfDNA sequencing for quantitating viral loads through detection of fragments that would be unrecoverable by qPCR.

Emerging respiratory infections: The infectious disease pathology of SARS, MERS, pandemic influenza, and Legionella.

Lower respiratory infections remain one of the top global causes of death and the emergence of new diseases continues to be a concern. In the first two decades of the 21st century, we have born witness to the emergence of newly recognized coronaviruses that have rapidly spread around the globe, including severe acute respiratory syndrome virus (SARS) and Middle Eastern respiratory syndrome virus (MERS). We have also experienced the emergence of a novel H1N1 pandemic influenza strain in 2009 that caused substantial morbidity and mortality around the world and has transitioned into a seasonal strain. Although we perhaps most frequently think of viruses when discussing emerging respiratory infections, bacteria have not been left out of the mix, as we have witnessed an increase in the number of infections from Legionella spp. since the organisms' initial discovery in 1976. Here, we explore the basic epidemiology, clinical presentation, histopathology, and clinical laboratory diagnosis of these four pathogens and emphasize themes in humans' evolving relationship with our natural environment that have contributed to the infectious burden. Histology alone is rarely diagnostic for these infections, but has been crucial to bettering our understanding of these diseases. Together, we rely on the diagnostic acumen of pathologists to identify the clinicopathologic features that raise the suspicion of these diseases and lead to the early control of the spread in our populations.

Complex Regional Pain Syndrome after Total Knee Arthroplasty is Rare and Misdiagnosis Potentially Hazardous-Prospective Study of the New Diagnostic Criteria in 100 Patients with No Cases Identified.

Previous studies suggest that complex regional pain syndrome (CRPS) occurs in up to 21% of patients following total knee arthroplasty (TKA). However, this diagnosis has a substantial impact on the patient's management if it is incorrect. We aimed to identify cases, using updated internationally accepted criteria, while investigating potential causes of misdiagnosis.We prospectively studied a consecutive series of 100 primary TKA patients. Each patient was assessed 6-week post-TKA. Pain levels were recorded with the presence of symptoms and signs of CRPS (Budapest Diagnostic Criteria) assessed in those with excessive pain. An alternative diagnosis was sought, in these patients, including the presence of neuropathic pain.We found no cases of CRPS (no patients had symptoms or signs in greater than two of four subgroups). Seventeen patients had excessive pain levels (nine had an alternative diagnosis explaining this). The commonest signs were sensory and sudomotor, whereas motor/trophic changes were not seen. Using a previous definition (Orlando Criteria), eight patients may have been diagnosed with CRPS. Over half of the patients with unexplained excessive pain had evidence of neuropathic pain.CRPS is a rare diagnosis following TKA using modern criteria. Isolated signs and symptoms may lead to the overdiagnosis of CRPS in the presence of unexplained pain following TKA. New diagnostic criteria, with strict definitions and treatment algorithms, are now accepted. Delays in managing more common causes (such as neuropathic pain) may negatively affect the patient's outcome.

Groupness in Preverbal Infants: Proof of Concept.

Infant sociability is generally conceived in terms of dyadic capacities and behaviors. Recently, quantitative evidence has been published to support arguments that infants achieve a criterion for groupness: the capacity to interact simultaneously with two others. Such studies equate this capacity with alternating dyadic acts to the two other members of an interacting trio. Here we propose a stricter threefold criterion for infant groupness, of which the crux is whether the social behavior of an infant at time B is shown to be influenced by what two or more group-members were previously doing at time A. We test the viability of this conceptualization: (a) through its justification of the novel laboratory procedure of studying infant sociability in infant-peer quartets (rather than trios); and, (b) in an analysis of a pilot study of gaze-behavior recorded in 5-min interactions among two quartets of infants aged 6-9 months. We call this a 'proof of concept' because our aim is to show that infants are capable of groupness, when groupness is conceptualized in a supra-dyadic way-not that all infants will manifest it, nor that all conditions will produce it, nor that it is commonplace in infants' everyday lives. We found that both quartets did achieve the minimum criterion of groupness that we propose: mutual gaze predicting coordinated gaze (where two babies, A and B, are looking at each other, and B is then looked at by C, and sometimes D) more strongly than the reverse. There was a significant absence of 'parallel mutual gaze,' where the four babies pair off. We conclude that, under specific conditions, preverbal infants can manifest supra-dyadic groupness. Infants' capacities to exhibit groupness by 9 months of age, and the paucity of parallel mutual gaze in our data, run counter to the assumption that infant sociability, when in groups, is always generated by a dyadic program. Our conceptualization and demonstration of groupness in 8-month-olds thus opens a host of empirical, theoretical, and practical questions about the sociability and care of young babies.