Host genetic variants associated with COVID-19 reconsidered in a Slovak cohort.

We present the results of an association study involving hospitalized coronavirus disease 2019 (COVID-19) patients with a clinical background during the 3rd pandemic wave of COVID-19 in Slovakia. Seventeen single nucleotide variants (SNVs) in the eleven most relevant genes, according to the COVID-19 Host Genetics Initiative, were investigated. Our study confirms the validity of the influence of LZTFL1 and 2'-5'-oligoadenylate synthetase (OAS)1/OAS3 genetic variants on the severity of COVID-19. For two LZTFL1 SNVs in complete linkage disequilibrium, rs17713054 and rs73064425, the odds ratios of baseline allelic associations and logistic regressions (LR) adjusted for age and sex ranged in the four tested designs from 2.04 to 2.41 and from 2.05 to 3.98, respectively. The OAS1/OAS3 haplotype 'gttg' carrying a functional allele G of splice-acceptor variant rs10774671 manifested its protective function in the Delta pandemic wave. Significant baseline allelic associations of two DPP9 variants in all tested designs and two IFNAR2 variants in the Omicron pandemic wave were not confirmed by adjusted LR. Nevertheless, adjusted LR showed significant associations of NOTCH4 rs3131294 and TYK2 rs2304256 variants with severity of COVID-19. Hospitalized patients' reported comorbidities were not correlated with genetic variants, except for obesity, smoking (IFNAR2), and hypertension (NOTCH4). The results of our study suggest that host genetic variations have an impact on the severity and duration of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Considering the differences in allelic associations between pandemic waves, they support the hypothesis that every new SARS-CoV-2 variant may modify the host immune response by reconfiguring involved pathways.

Esophageal Infusion of Menthol Does Not Affect Esophageal Motility in Patients with Gastroesophageal Reflux Disease.

Menthol is thought to trigger gastroesophageal reflux disease (GERD) symptoms by influencing esophageal peristalsis and lower esophageal sphincter (LES) function. We evaluated the effect of esophageal menthol infusion on esophageal motility and the LES in healthy volunteers and in patients with GERD. High resolution manometry (HRM) catheter with attached thin tube for menthol infusion was placed transnasally. Protocol which included baseline recording, 16 water swallows (5 ml, 10 ml, and 15 ml) and the multiple rapid swallows was performed before and after esophageal infusion of menthol (3 mM, 20 min, 8 ml/min). We evaluated the effect of this infusion on the HRM parameters of esophageal peristalsis (distal contractile integral, distal latency, contractile front velocity) and the lower esophageal sphincter (LES) barrier function (integrated relaxation pressure and the inspiratory augmentation of the LES). Simultaneously we evaluated the quality and intensity of the symptoms during the menthol infusion. Esophageal infusion of menthol did not appreciably affect HRM measurements characterizing esophageal peristalsis and LES pressure in healthy subjects (N = 13) or GERD patients (N = 11). The magnitude of the distal contractile integral (5 ml) was changed neither in the healthy volunteers' group, (735 ± 127 vs. 814 ± 117 mmHg, p = 0.5), nor in the GERD patients (295 ± 78 vs. 338 ± 96 mmHg, p = 0.99). In healthy volunteers menthol did not change the inspiratory augmentation of the LES (8.67 ± 1.09 vs. 7.69 ± 0.96 mmHg, p = 0.15) and neither did for GERD patients (8.8 ± 1.18 vs. 8.22 ± 0.91 mmHg, p = 0.43). We observed no significant difference in any HRM parameter following menthol infusion, except for distal latency in 10 ml swallows. By contrast, menthol infusion induced significantly more intense discomfort in GERD patient than in healthy volunteers. Our results suggest no significant temporal effect of menthol on the esophageal motility or LES function, neither in healthy volunteers, nor in GERD. Arguably, other mechanisms are responsible for menthol-related heartburn.

Idiopathic Pan-Colonic and Small-Intestine Varices.

Idiopathic colonic varices represent a rare source of gastrointestinal haemorrhage with a presumed incidence around 0.0007%. Herein, we present a case of idiopathic colonic and small-intestine varices. According to our knowledge, this case report is the first description of both pan-colonic and small-intestine idiopathic varices of this extent. A young male patient without any previous notable medical history was admitted to the hospital because of massive enterorrhagia with haemodynamic instability. Colonoscopy revealed massive pan-colonic varices. After stabilization, numerous diagnostic procedures were performed in order to investigate the aetiology of pan-colonic varices without any explanation of the patient's condition. In addition, capsule endoscopy revealed varices through the whole length of the small intestine. The final diagnosis was idiopathic varices of the colon and small intestine. Because of the rapid clinical stabilization, the single incident of haemorrhage and the extension of the disease, a conservative approach was chosen (venotonics and ß-blockers). During the 12-month follow-up period, the patient reported no gastrointestinal haemorrhage.

Primer: histopathology of polyomavirus-associated nephropathy in renal allografts.

The BK polyomavirus exhibits tropism for the renal tubular epithelium, where it establishes latent infection. Vigorous immunosuppression of renal allograft recipients can lead to reactivation of the infection and the development of polyomavirus-associated nephropathy (PVAN). Clinically, gradually decreasing renal function, viremia and viruria are observed several months after transplantation; allograft failure occurs in 1-10% of patients. Definitive diagnosis requires an allograft biopsy. Histologically, viral replication results in tubular epithelial cell enlargement, karyomegaly and nuclear inclusion bodies. The cytopathic changes are often associated with lysis of tubular epithelial cells, denudation of the basement membrane and an interstitial inflammatory response. The involvement is multifocal; distal nephron segments are more severely affected than proximal segments. Changes observed during light microscopy are suggestive but not pathognomonic for PVAN, and the diagnosis must be confirmed by adjunct studies. Adjunct studies consist of immunohistochemistry on paraffin sections using an antibody to the SV40 large T antigen, or electron microscopy of infected tubular epithelial cells (virions 40 nm in diameter). PVAN manifests in three histologic patterns: pattern A, viral cytopathic changes with no or only minimal inflammation; pattern B, cytopathic and cytolytic lesions with interstitial inflammation; or pattern C, predominantly interstitial fibrosis and tubular atrophy, with variable cytopathic and inflammatory changes. These patterns correlate with clinical outcomes.

Primer: Histopathology of calcineurin-inhibitor toxicity in renal allografts.

Calcineurin inhibitors (ciclosporin and tacrolimus) can cause acute and chronic nephrotoxicity. The serum levels of these drugs do not correlate well with the extent of renal damage caused, and the clinical manifestation is nonspecific. Renal biopsy is a reliable tool with which to diagnose calcineurin-inhibitor-induced nephrotoxicity. Ciclosporin and tacrolimus produce identical lesions, which are focal in nature and can be overlooked, necessitating the evaluation of serial tissue sections. Acute toxicity is characterized histologically by necrosis and early hyalinosis of individual smooth muscle cells in the afferent arterioles, and/or isometric vacuolation of the proximal straight tubules; thrombotic microangiopathy is a rare manifestation. In chronic toxicity, the damaged media smooth muscle cells in afferent arterioles are replaced by beaded medial hyaline deposits that bulge into the adventitia; the interstitium displays striped fibrosis and tubular atrophy. As maintenance doses of calcineurin inhibitors in renal transplant recipients have been lowered during the past decade, the incidence of acute toxicity has decreased markedly. Chronic toxicity, however, is still prevalent, and causes chronic allograft damage.