Inflammatory biomarkers at hospital discharge are associated with readmission and death in patients hospitalized for COVID-19

European Journal of Clinical Microbiology & Infectious Diseases -     

Diagnostic accuracy of VIDISCA-NGS in patients with suspected central nervous system infections

ObjectivesConfirming the diagnosis in viral central nervous system (CNS) infections can be difficult with the currently available diagnostic tools. Virus discovery cDNA-amplified fragment length polymorphism next-generation sequencing (VIDISCA-NGS) is a promising viral metagenomic technique that enables the detection of all viruses in a single assay. We performed a retrospective study on the diagnostic accuracy of VIDISCA-NGS in cerebrospinal fluid (CSF) of individuals with suspected CNS infections.MethodsConsecutive adult patients presenting to the Emergency Department or inpatients, who underwent a lumbar puncture for the suspicion of a CNS infection, were included if they were diagnosed with a viral CNS infection, or if a viral CNS infection was initially suspected but eventually a different diagnosis was made. A quantitative PCR panel of the most common causative viruses was performed on CSF of these patients as reference standard and compared with the results of VIDISCA-NGS, the index test.ResultsWe included 38 individuals with viral CNS infections and 35 presenting with suspected CNS infection for whom an alternative aetiology was finally established. Overall sensitivity and specificity were 52% (95% CI 31%–73%) and 100% (95% CI 91%–100%), respectively. One enterovirus, detected by VIDISCA-NGS, was only identified by quantitative PCR upon retesting. Additional viruses identified by VIDISCA-NGS consisted of GB virus C, human papillomavirus, human mastadenovirus C, Merkel cell polyoma virus and anelloviruses.ConclusionIn patients for whom routine diagnostics do not yield a causative pathogen, VIDISCA-NGS can be of additional value as it can detect a broader range of viruses, but it does not perform well enough to replace quantitativePCR.     

In vivo HIV-1 infection of CD45RA(+)CD4(+) T cells is established primarily by syncytium-inducing variants and correlates with the rate of CD4(+) T cell decline

Switch from non-syncytium-inducing (NSI) to syncytium-inducing (SI) HIV type 1 (HIV-1) is associated with accelerated CD4(+) T cell depletion, which might partially be explained by higher virulence of SI variants compared with NSI variants. Because NSI and SI variants use different coreceptors for entry of target cells, altered tropism might offer an explanation for increased pathogenesis associated with SI HIV-1 infection. To investigate whether SI and NSI HIV-1 variants infect different CD4(+) T cell subsets in vivo, the distribution of SI and NSI variants over CD4(+) memory (CD45RA(-)RO(+)) and naive (CD45RA(+)RO(-)) cells was studied by using limiting dilution cultures. In contrast to NSI variants that were mainly present in CD45RO(+) cells, SI variants were equally distributed over CD45RO(+) and CD45RA(+) cells. Infection of memory cells by both NSI and SI HIV-1 and infection of naive cells primarily by SI HIV-1 corresponded closely with the differential cell surface expression of CXCR4 and CCR5. The frequency of SI-infected CD45RA(+) CD4(+) T cells, but not the frequency of NSI- or SI-infected CD45RO(+) CD4(+) T cells, correlated with the rate of CD4(+) T cell depletion. Infection of naive cells by SI HIV-1 may interfere with CD4(+) T cell production and thus account for rapid CD4(+) T cell depletion.     

Toxicity of Amphotericin B Deoxycholate-Based Induction Therapy in Patients with HIV-Associated Cryptococcal Meningitis

Amphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia. Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome. In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days. Serum creatinine levels increased by 37 μmol/liter (95% CI, 30 to 45 μmol/liter) by day 7 and by 49 μmol/liter (95% CI, 35 to 64μmol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 μmol, and 6% discontinued AmBd prematurely. The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3; P = 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11; P = 0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect. The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility.     

Commentary: Periodontitis and Rheumatoid Arthritis: What Do We Know?

Background: Currently, in the field of rheumatology, there is much attention given towards the possible causality between periodontitis and rheumatoid arthritis (RA), specifically regarding the role of Porphyromonas gingivalis (Pg). This bacterium is unique, having a citrullinating enzyme. Antibodies against citrullinated proteins are rather specific for RA. Methods: Because causality is ultimately tested in longitudinal cohort studies which currently do not exist for periodontitis and RA, this commentary applied Bradford Hill criteria on the existing literature to assess causality as the most likely interpretation of this association. Conclusions: From an epidemiologic point of view, patients with RA have a higher incidence of periodontal disease than individuals without RA. In addition, there is a dose‐response pattern in the association between the severity of periodontitis and RA disease activity. There are indications that periodontitis precedes RA, but there is no evidence yet available to show that Pg plays a direct role in this temporal relationship. The role of the unique characteristic of citrullination by Pg remains unexplained. However, in animal models, citrullination by Pg plays a distinct role in the development and aggravation of experimental arthritis. Although the role of Pg in RA remains speculative, a causative role for periodontitis as a chronic inflammatory disease caused by infectious agents in RA seems biologically plausible.     

A 3-base pair deletion,c.9711_9713del,in DMD results in intellectual disability without muscular dystrophy

We have identified a deletion of 3 base pairs in the dystrophin gene (DMD), c.9711_9713del, in a family with nonspecific X-linked intellectual disability (ID) by sequencing of the exons of 86 known X-linked ID genes. This in-frame deletion results in the deletion of a single-amino-acid residue, Leu3238, in the brain-specific isoform Dp71 of dystrophin. Linkage analysis supported causality as the mutation was present in the 7.6 cM linkage interval on Xp22.11–Xp21.1 with a maximum positive LOD score of 2.41 (MRX85 locus). Molecular modeling predicts that the p.(Leu3238del) deletion results in the destabilization of the C-terminal domain of dystrophin and hence reduces the ability to interact with β-dystroglycan. Correspondingly, Dp71 protein levels in lymphoblastoid cells from the index patient are 6.7-fold lower than those in control cell lines (P=0.08). Subsequent determination of the creatine kinase levels in blood of the index patient showed a mild but significant elevation in serum creatine kinase, which is in line with impaired dystrophin function. In conclusion, we have identified the first DMD mutation in Dp71 that results in ID without muscular dystrophy.     

Cognitive bias in action: Evidence for a reciprocal relation between confirmation bias and fear in children

Background and objectives

Some cognitive models propose that information processing biases and fear are reciprocally related. This idea has never been formally tested. Therefore, this study investigated the existence of a vicious circle by which confirmation bias and fear exacerbate each other.

Methods

One-hundred-and-seventy-one school children (8–13 years) were first provided with threatening, ambiguous, or positive information about an unknown animal. Then they completed a computerized information search task during which they could collect additional (negative, positive, or neutral) information about the novel animal. Because fear levels were repeatedly assessed during the task, it was possible to examine the reciprocal relationship between confirmation bias and fear.

Results

A reciprocal relation of mutual reinforcement was found between confirmation bias and fear over the course of the experiment: increases in fear predicted subsequent increases in the search for negative information, and increases in the search for negative information further enhanced fear on a later point-in-time. In addition, the initial information given about the animals successfully induced diverging fear levels in the children, and determined their first inclination to search for additional information.

Limitations

As this study employed a community sample of primary school children, future research should test whether these results can be generalized to clinically anxious youth.

Conclusions

These findings provide first support for the notion that fearful individuals may become trapped in a vicious circle in which fear and a fear-related confirmation bias mutually strengthen each other, thereby maintaining the anxiety pathology.     

Construction and in vivo evaluation of a dual layered collagenous scaffold with a radial pore structure for repair of the diaphragm

In each organ the extracellular matrix has a specific architecture and composition, adapted to the functional needs of that organ. As cells are known to respond to matrix organization, biomaterials that take into account the specific architecture of the tissues to be regenerated may have an advantage in regenerative medicine. In this study we focussed on the diaphragm, an organ essential for breathing, and consisting of radial oriented skeletal muscle fibres diverging from a central tendon plate. To mimic this structure dual layered collagenous scaffolds were constructed with a radial pore orientation, prepared by inward out freezing, and reinforced by a layer of compressed collagen. Similar scaffolds with a random round pore structure were taken as controls. Scaffolds were first mildly crosslinked by formaldehyde vapour fixation for initial stabilization (13% and 17% crosslinking for the radial and control scaffolds, respectively), and further crosslinked using aqueous 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide (38% and 37% crosslinking, respectively). Scaffolds were implanted into a surgically created diaphragm defect in rats and explanted after 12 weeks. Macroscopically, integration of the radial scaffolds with the surrounding diaphragm was better compared with the controls. Cells had infiltrated further into the centre of the scaffolds (P = 0.029) and there was a tendency of blood vessels to migrate deeper into the radial scaffolds (P = 0.057, compared with controls). Elongated cells (SMA-positive) were aligned with the radial structures. In conclusion, collagenous scaffolds with a stable radial pore structure can be constructed which facilitate cellular in-growth and alignment in vivo.     

Postoperative recurrence of Crohn’s disease: impact of endoscopic monitoring and treatment step‐up

Aim Eighty per cent of patients with Crohn’s disease require surgery, of whom 70% will require a further operation. Recurrence occurs at the anastomosis. Although often recommended, the impact of postoperative colonoscopy and treatment adjustment is unknown. Method Patients with a bowel resection over a 10‐year period were reviewed and comparison made between those who did and did not have a postoperative colonoscopy within 1 year of surgery, and those who did or did not have a step‐up in drug therapy. Results Of 222 patients operated on, 136 (65 men, mean age 33 years, mean disease duration 8 years, median follow‐up 4 years) were studied. Of 70 patients with and 66 without postoperative colonoscopy, clinical recurrence occurred in 49% and 48% (NS) and further surgery in 9% and 5% (NS). Eighty‐nine per cent of colonoscoped patients had a decision based on the colonoscopic findings: of these, 24% had a step‐up of drug therapy [antibiotics (n = 10), aminosalicylates (n = 2), thiopurine (n = 5), methotrexate (n = 1)] and 76% had no step‐up in drug therapy. In colonoscoped patients clinical recurrence occurred in 9 (60%) of 15 patients with, and 23 (49%) of 47 without step‐up and surgical recurrence in 2 (13%) of 15 and 4 (9%) of 47 (NS). Conclusion Clinical recurrence occurs in a majority of patients soon after surgery. In this cohort, there was no clinical benefit from colonoscopy or increased drug therapy within 1 year after operation. However, the response to the endoscopic findings was not standardized and immunosuppressive therapy was uncommon. Standardizing timing of colonoscopy and drug therapy, including more intense therapy, may improve outcome, although this remains to be proven.