Hepatocellular liver injury in hospitalized patients affected by COVID-19: Presence of different risk factors at different time points.

BACKGROUND: Prevalence and clinical impact of increased liver function tests in patients affected by Coronavirus disease 2019 (COVID-19) is controversial. AIMS: This observational study evaluates the prevalence of transaminases elevation in hospitalized patients affected by COVID-19 and investigates the presence of factors associated with hepatocellular injury and with mortality. METHODS: Data of 292 adult patients with confirmed COVID-19 admitted to the Ente Ospedaliero Cantonale (Switzerland) were retrospectively analyzed. RESULTS: Transaminases were increased in about one-third of patients on hospital admission and two-thirds of patients during the hospital stay. On hospital admission, transaminases were more commonly elevated in younger patients, who also reported elevated C reactive protein and a higher degree of respiratory failure. Independent factors associated with abnormal transaminases during hospitalization were drugs, in particular paracetamol (OR=2.67; 95% CI=1.38-5.18; p = 0.004) and remdesivir (OR=5.16; 95% CI=1.10-24.26; p = 0.04). Mortality was independently associated to age (OR = 1.09; 95% CI=1.05-1.13; p<0.001), admission to intensive care unit (OR=5.22; 95% CI=2.28-11.90; p<0.001) and alkaline phosphatase peak (OR=1.01; 95% CI=1.00- 1.01; p = 0.01). CONCLUSIONS: On hospital admission, factors associated with liver damage were linked to demographic and clinical characteristics (age, inflammation and hypoxia) while, during hospitalization, drug treatment was related to development and progression of hepatocellular damage. Mortality was associated with alkaline phosphate peak value.

Stroke Mimics in the Acute Setting: Role of Multimodal CT Protocol.

BACKGROUND AND PURPOSE: Ischemic stroke can be mimicked by nonischemic conditions. Due to emphasis on the rapid treatment of acute ischemic stroke, it is crucial to identify these conditions to avoid unnecessary therapies and potential complications. We investigated the performance of the multimodal CT protocol (unenhanced brain CT, CTA, and CTP) to discriminate stroke mimics from acute ischemic stroke. MATERIALS AND METHODS: We retrospectively selected multimodal CT studies performed for clinical suspicion of acute ischemic stroke in our center in a 24-month period, including patients with at least 1 follow-up imaging study (brain CT or MR imaging). Hemorrhagic strokes were excluded. We measured the performance of multimodal CT, comparing the original diagnostic results with the final clinical diagnosis at discharge. RESULTS: Among 401 patients, a stroke mimic condition was diagnosed in 89 (22%), including seizures (34.8%), migraine with aura attack (12.4%), conversion disorder (12.4%), infection (7.9%), brain tumor (7.9%), acute metabolic condition (6.7%), peripheral vertigo (5.6%), syncope (5.6%), transient global amnesia (3.4%), subdural hematoma (1.1%), cervical epidural hematoma (1.1%), and dural AVF (1.1%). Multimodal CT sensitivity, specificity, and accuracy were 24.7%, 99.7%, and 83%. Multimodal CT revealed peri-ictal changes in 13/31 seizures and diagnosed 7/7 brain tumors, 1/1 dural AVF, and 1/1 subdural hematoma. CT perfusion played a pivotal diagnostic role. CONCLUSIONS: Multimodal CT demonstrated low sensitivity but high specificity in the diagnosis of stroke mimics in the acute setting. The high specificity of multimodal CT allows ruling out stroke and thereby avoiding unnecessary revascularization treatment in patients with diagnosis of a stroke mimic.

A de novo frameshift in HNRNPK causing a Kabuki-like syndrome with nodular heterotopia.

Kabuki syndrome is a heterogeneous condition characterized by distinctive facial features, intellectual disability, growth retardation, skeletal abnormalities and a range of organ malformations. Although at least two major causative genes have been identified, these do not explain all cases. Here we describe a patient with a complex Kabuki-like syndrome that included nodular heterotopia, in whom testing for several single-gene disorders had proved negative. Exome sequencing uncovered a de novo c.931_932insTT variant in HNRNPK (heterogeneous nuclear ribonucleoprotein K). Although this variant was identified in March 2012, its clinical relevance could only be confirmed following the August 2015 publication of two cases with HNRNPK mutations and an overlapping phenotype that included intellectual disability, distinctive facial dysmorphism and skeletal/connective tissue abnormalities. Whilst we had attempted (unsuccessfully) to identify additional cases through existing collaborators, the two published cases were 'matched' using GeneMatcher, a web-based tool for connecting researchers and clinicians working on identical genes. Our report therefore exemplifies the importance of such online tools in clinical genetics research and the benefits of periodically reviewing cases with variants of unproven significance. Our study also suggests that loss of function variants in HNRNPK should be considered as a molecular basis for patients with Kabuki-like syndrome.

Physical restraint in the ICU: does it prevent device removal?

BACKGROUND: Physical restraint is frequently used in the intensive care setting but little is known regarding its clinical scenario and effectiveness in preventing adverse events (AEs), defined as device removal. METHODS: We carried out a prospective observational study in three Intensive Care Units on 120 adult high-risk patients. The effectiveness of physical restraint was evaluated using the propensity score methodology in order to obtain comparable groups. RESULTS: Physical restraint was applied in 1371 of 3256 (43%) nurse shifts accounting for 120 patients. Substantial agitation, the nurse's judgement of insufficient sedation and sedative drug reduction were positively associated with physical restraint, whereas the presence of analgesics at admission, increased disease gravity and the treating hospital as the most substantial variable showed a negative association. Eighty-six AEs were observed in 44 patients. Quiet (SAS=1-4), unrestrained patients accounted for 40 cases, and agitated (SAS≥5) but physically restrained patients for 17 cases. The presence of any type of physical restraint had a protective effect against any type of AE (OR=0.28; CI 0.16-0.51). The observed AEs showed a limited impact on the patients' course of illness. No physical harm related to physical restraint was reported. CONCLUSION: Physical restraint efficiently averts AEs. Its application is mainly driven by local habits. Typically, the almost recovered, apparently calm and hence unrestrained patient is at greatest risk for undesirable device removal. The control/interpretation of the patient's analgo-sedation might be inappropriate.

Potential predictors of visiting hours policies in the intensive care setting.

BACKGROUND: Restrictions on visiting hours in the intensive care unit (ICU) are usually adopted worldwide. Current knowledge shows that these limitations are not necessary. In order to identify potential variables that are associated with restricted visiting times we carried out an observational study on visiting policy. METHODS: We conducted a questionnaire-based nationwide survey among all certified adult Swiss ICUs. An electronic questionnaire was sent by e-mail between May and June 2012 to all chief nurses. Length of permitted visiting time was taken as main endpoint to assess the association with different potential predictor variables using simple and multiple linear regression analysis. RESULTS: Response rate was 73 of 75 ICUs (97%). Only two ICUs (3%) have an unrestricted visiting policy. Median daily visiting time was 8 hours (range: 1.5 to 24 hours; interquartile range: 6-10 hours). Simple and multiple linear regression analysis demonstrated a significant effect in visiting hours between Italian- and French-speaking parts of Switzerland with 4.0 hours longer visiting hours in the former (P=0.039) without identifying other predictors. CONCLUSION: Swiss ICUs have less restrictive visiting policies compared to other Western countries; nevertheless very few Swiss ICUs have unrestricted visitations. Neither medical type of ICU, nor ICU infrastructure was determining the visiting policy in Swiss intensive care setting. Cultural factors, as captured by the linguistic areas are the only identified predictors of visiting hours. Since the current policy is not justified by clinical outcomes but based only on cultural settings, it needs to be definitively reconsidered and unrestricted visiting policies must become the rule rather than the exception.

ARDS with septic shock due to Legionella longbeachae pneumonia in a patient with polymyalgia rheumatica.

  Legionella longbeachae is a very uncommon cause of community acquired pneumonia in Western countries. L. longbeachae does not grow on blood agar media and is usually not detected by sputum gram stain or blood culture. Furthermore Legionella urinary antigen testing fails to detect it. In this report we described a 79-year-old man with polymyalgia rheumatica under systemic corticosteroid treatment without other additional risk factors who developed a cultured-proven L. longbeachae community-acquired pneumonia complicated by an acute respiratory distress syndrome with septic shock. This case report demonstrates that non-pneumophila Legionella species must be taken into account as casual agents of community acquired pneumonia even in mild immunosuppressed patients, and empiric anti-Legionella antimicrobial coverage might be indicated until Legionella has definitively been rule out by adequate testing.

High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility.

Autism spectrum disorders are a group of highly heritable neurodevelopmental disorders with a complex genetic etiology. The International Molecular Genetic Study of Autism Consortium previously identified linkage loci on chromosomes 7 and 2, termed AUTS1 and AUTS5, respectively. In this study, we performed a high-density association analysis in AUTS1 and AUTS5, testing more than 3000 single nucleotide polymorphisms (SNPs) in all known genes in each region, as well as SNPs in non-genic highly conserved sequences. SNP genotype data were also used to investigate copy number variation within these regions. The study sample consisted of 127 and 126 families, showing linkage to the AUTS1 and AUTS5 regions, respectively, and 188 gender-matched controls. Further investigation of the strongest association results was conducted in an independent European family sample containing 390 affected individuals. Association and copy number variant analysis highlighted several genes that warrant further investigation, including IMMP2L and DOCK4 on chromosome 7. Evidence for the involvement of DOCK4 in autism susceptibility was supported by independent replication of association at rs2217262 and the finding of a deletion segregating in a sib-pair family.

Single arterial occlusion to locate resistance in patients with pulmonary hypertension.

The purpose of this study was to determine the site of increased resistance using the arterial occlusion technique in patients with severe pulmonary hypertension. Pulmonary vascular resistance was partitioned in arterial and venous components based on double exponential fitting analysis of the pulmonary artery pressure decay curve: after balloon occlusion in 36 patients with pulmonary arterial hypertension (PAH); at baseline and during the inhalation of 20 parts per million of nitric oxide (NO); in four patients with chronic thromboembolic pulmonary hypertension; and in two patients with pulmonary veno-occlusive disease. In the patients with PAH, at baseline, mean pulmonary artery pressure was 56+/-2 mmHg (mean+/-SE), with an arterial component of resistance of 63+/-1%. Inhaled NO did not change the partition of resistance. The arterial component of resistance amounted on average to 42% and 77% in the patients with veno-occlusive disease and the patients with thromboembolic pulmonary hypertension, respectively. However, the partitioning of resistance did not discriminate between these three diagnostic categories. The occlusion technique may help to locate the predominant site of increased resistance in patients with severe pulmonary hypertension, but does not allow for a satisfactory differential diagnosis on an individual basis.

Extreme length and length variation in the first ribosomal internal transcribed spacer of ladybird beetles (Coleoptera: Coccinellidae).

DNA sequences of the first ribosomal internal transcribed spacer (ITS1) were isolated from 10 ladybird beetle species (Coleoptera: Coccinellidae) representing four subfamilies (Coccinellinae, Chilocorinae, Scymninae, and Coccidulinae). The spacers ranged in length from 791 to 2,572 bp, thereby including one of the longest ITS1s and exhibiting one of the most extreme cases of ITS1 size variation in eukaryotes recorded to date. The causes of length variation were therefore analyzed. Almost no putatively homologous sequence similarities were identified for the taxa included. The only exception was for the subfamily Coccinellinae, which yielded sequence similarities in six regions of approximately 550 nucleotide positions, primarily at the 5' and 3' ends of ITS1. The majority of differences in ITS1 length between taxa could be attributed to the presence of repetitive elements with comparatively long repeat units. Repetition arose several times independently and was confined to the middle of the spacer which, in contrast to the 5' and 3' ends, had not been inferred in previous studies to be subject to functional constraints. These elements were characterized by high rates of evolutionary change, most likely as a result of high substitution rates in combination with inefficient homogenization across repeats. The repeated origin and subsequent divergence of "long" repetitive elements should thus be assumed to be an important factor in the evolution of coccinellid ITS1.

Genetic analysis of the connexin-26 M34T variant: identification of genotype M34T/M34T segregating with mild-moderate non-syndromic sensorineural hearing loss.

Mutations in the human gap junction beta-2 gene (GJB2) that encodes connexin-26 have been shown to cause non-syndromic sensorineural hearing loss (NSSNHL) at the DFNB1 locus on 13q11. Functional and genetic data regarding the disease causing potential of one particular GJB2 sequence variant, 101 T-->C (M34T), have proven contradictory. In this study, we found the prevalence of the M34T allele in a cohort of white sib pairs and sporadic cases with NSSNHL from the United Kingdom and Ireland to be 3.179% of chromosomes screened. Significantly, we identified the first M34T/M34T genotype cosegregating in a single family with mid to high frequency NSSNHL. Screening a control population of 630 subjects we identified 25 M34T heterozygotes; however, no M34T homozygotes were detected. Surprisingly, the majority of M34T alleles (88%) were in cis with a 10 bp deletion in the 5' non-coding sequence. This non-coding deletion was also homozygous in the homozygous M34T subjects. Microsatellite analysis of flanking loci in M34T heterozygotes and controls does not define an extensive ancestral haplotype but preliminary data suggest two common alleles in subjects with the M34T allele. In summary, we provide data that support M34T acting as a recessive GJB2 allele associated with mild-moderate prelingual hearing impairment.

Continuous versus pulsatile pulmonary hemodynamics in canine oleic acid lung injury.

Pulmonary hypertension occurs commonly in the acute respiratory distress syndrome (ARDS), but associated right ventricular failure is relatively rare. We tested the hypothesis that this apparent contradiction is explained by a peripheral location of the increased pulmonary vascular resistance (Rpva). Experimental ARDS was induced in eight dogs by injection of oleic acid (0.07 ml/kg). Changes in Rpva were evaluated by measurements of pulmonary artery pressure (Ppa) at several levels of flow (Q), which was altered by manipulation of venous return. The analysis of Ppa decay curves after arterial balloon occlusion was used to partition Rpva into arterial and venous segments. Right ventricular afterload was evaluated by determination of pulmonary vascular impedance (Zpva), which was calculated from spectral analysis of Ppa and Q waves. Oleic acid lung injury was associated with an increase in both the slope and the extrapolated pressure intercept of Ppa/Q plots, no change in the partitioning of Rpva, no change in time-domain indices in wave reflection or in pulmonary arterial compliance, and a decrease in both the characteristic impedance and pulsatile component of total right ventricular hydraulic load. We conclude that the site of increased Rpva in oleic acid lung injury is the smallest pulmonary arterioles, which, together with a decreased characteristic impedance, contributes to minimize right ventricular afterload.

A lack of a functional NAD(P)H:quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions. United Kingdom Childhood Cancer Study Investigators.

Rearrangements and fusion of the MLL gene with various alternative partner genes occur in approximately 80% of infant leukemias and are acquired during fetal hemopoiesis in utero. Similar MLL gene recombinants also occur in topoisomerase II-inhibiting drug-induced leukemias. These data have led to the suggestion that some infant leukemia may arise via transplacental fetal exposures during pregnancy to substances that form cleavable complexes with topoisomerase II and induce illegitimate recombination of the MLL gene. A structural feature shared by many topoisomerase II-inhibiting drugs and other chemicals is the quinone moiety. We assayed, by PCR-RFLP, for a polymorphism in an enzyme that detoxifies quinones, NAD(P)H:quinone oxidoreductase (NQO1), in a series (n = 36) of infant leukemias with MLL rearrangements versus unselected cord blood controls (n = 100). MLL-rearranged leukemias were more likely to have genotypes with low NQO1 function (heterozygous CT or homozygous TT at nucleotide 609) than controls (odds ratio, 2.5; P = 0.015). In contrast, no significant allele bias was seen in other groups of pediatric leukemias with TEL-AML1 fusions (n = 50) or hyperdiploidy (n = 29). In the subset of infant leukemias that had MLL-AF4 fusion genes (n = 21), the bias increase in low or null function NQO1 genotypes was more pronounced (odds ratio, 8.12; P = 0.00013). These data support the idea of a novel causal mechanism in infant leukemia involving genotoxic exposure in utero and modulation of impact on a selective target gene by an inherited allele encoding a rate-limiting step in a carcinogen detoxification pathway.

[Point of view on doping]. / Point de vue sur le dopage.

Doping is defined as the administration of or use by competing athletes of any substance foreign to the body or of any physiological substance taken in abnormal quantity or taken by an abnormal route of entry into the body with the sole intention of increasing in an artificial and unfair manner his/her performance in competition. The prevalence of doping has been estimated by rigorous methods to be 5-15%. The only two dopings of established efficacy are: anabolic steroids for resistive performance, and blood doping for endurance performance. Although medical control of athletes is reputably poor, reported accidents attributable to doping have been until now very rare. Doping is unfair, and must as such be banned from competitions. Medicalized doping is unethical. More studies are required to improve knowledge of doping as a public health issue. Sports medicine is in need of scientific and moral revalorization.

Electron dose calculation using multiple-scattering theory: thin planar inhomogeneities.

In this article in our series on electron dose calculation using multiple-scattering theory, we apply the Fermi-Eyges theory to the problem of a thin planar inhomogeneity present in an otherwise-layered medium. We derive expressions for the distribution function P and the location distribution L (which multiplied by the restricted mass collision stopping power is the dose directly deposited by the primary electrons) for various types of incident beams: a completely arbitrary distribution, a Gaussian point source, a pencil beam, an isotropic point source, and a broad parallel beam. We show how divergent-beam dose distributions can be determined from parallel-beam calculations, through use of equivalent configurations dependent upon the depth of dose calculation. Also, we indicate how this work can be applied to the design of wedges (or "compensators") for beam shaping to provide desired dose distributions or to match juxtaposed radiation fields. Explicit formulas for thin plates are then worked out, and we examine the appearance of hot and cold spots distal to the edge of a localized inhomogeneity, for thin half-slabs and for narrow strips. Finally, considering the case of a thin straight wedge-shaped inhomogeneity, we theoretically discover the phenomenon of a "focused hot spot" without an accompanying cold spot, and suggest the design of a "multiple-scattering lens".

Collimated electron beams and their associated penumbra widths.

The Fermi-Eyges multiple-scattering theory for electrons is applied to calculate profiles of collimated electron beams. The dose profile below the collimator is a convolution of the intensity distribution of the electrons at the level of the collimator and the distribution arising from the propagation of a Gaussian point source from the collimator to the level of the calculation. The electrons at the level of the collimator possess an angular distribution characteristic of the configuration of the electron beam at the vacuum window. Hence, the dose profile and its associated penumbra width can be expressed in terms of the angular moments of the distribution of the electrons at the collimator. The dependence of the penumbra width on the configuration-dependent angular spread of the electrons at the collimator accounts for differences in the size of the penumbra between two broad-beam configurations. These differences are also seen experimentally. We have also studied the dependence of the angular moments of the electrons upon scattering foils present above the collimator and the position of the beam-broadening device in the accelerator head.