COVID-19 in three waves in a tertiary referral hospital in Belgium: a comparison of patient characteristics, management, and outcome.

PURPOSE: Few studies have compared patient characteristics, clinical management, and outcome of patients with COVID-19 between the different epidemic waves. In this study, we describe patient characteristics, treatment, and outcome of patients admitted for COVID-19 in the Antwerp University Hospital over the first three epidemic waves of 2020-2021. METHODS: Retrospective observational study of COVID-19 patients in a Belgian tertiary referral hospital. All adult patients with COVID-19, hospitalized between February 29, 2020, and June 30, 2021, were included. Standardized routine medical data was collected from patient records. Risk factors were assessed with multivariable logistic regression. RESULTS: We included 722 patients, during the first (n = 179), second (n = 347) and third (n = 194) wave. We observed the lowest disease severity at admission during the first wave, and more elderly and comorbid patients during the second wave. Throughout the subsequent waves we observed an increasing use of corticosteroids and high-flow oxygen therapy. In spite of increasing number of complications throughout the subsequent waves, mortality decreased each wave (16.6%,15.6% 11.9% in 1st, 2nd and 3rd wave respectively). C-reactive protein above 150 mg/L was predictive for the need for intensive care unit admission (odds ratio (OR) 3.77, 95% confidence interval (CI) 2.32-6.15). A Charlson comorbidity index ≥ 5 (OR 5.68, 95% CI 2.54-12.70) and interhospital transfers (OR 3.78, 95% CI 2.05-6.98) were associated with a higher mortality. CONCLUSIONS: We observed a reduction in mortality each wave, despite increasing comorbidity. Evolutions in patient management such as high-flow oxygen therapy on regular wards and corticosteroid use may explain this favorable evolution.

Surgical management of a prolonged air leak after lung volume reduction surgery: technical aspects.

A prolonged air leak is a well-known complication after lung volume reduction surgery that increases hospital stays and morbidities. Adequate management of a prolonged air leak can be challenging, with some patients requiring reintervention. We describe the main technical aspects for identifying and sealing an alveolar-pleural fistula.

Vascular Graft Infections With Candida: A Factor for Increased Mortality in in-situ Reconstructions.

BACKGROUND: The empiric antibiotic regimen started after deep cultures and explantation of the graft mostly do not cover antifungals. We retrospectively studied the outcome of candida compared to non-candida VGI and assessed whether these results could justify the addition of antifungals to the empiric antibiotics in the early postoperative period. METHODS: All patients treated for infected aorto(ilio)femoral graft with excision and reconstruction at the vascular department of University Hospitals Leuven between January 2010 and 2017 (n = 56) were studied retrospectively. Patients were allocated to the candida group (n = 10) or non-candida group (n = 46) according to the presence of Candida in deep culture isolates. RESULTS: All-cause mortality was significantly higher in the candida group compared to the non-candida group. All-cause 30-day mortality was 40% and 13% for both groups respectively (P = 0.066). At 5 years this was 90% and 46% respectively (P = 0.014). In the candida group 6 patients (60%) had to be revised in the operating room due to bleeding, compared to 5 patients (11%) in the non-candida group (P = 0.002).  Two patients (20%) and 5 patients (11%) had to be readmitted to the ICU, respectively. CONCLUSION: Survival of candida related VGI is significantly worse, especially in the first 5 postoperative months. This could justify the addition of an antifungal to the early empiric postoperative antibiotic cocktail, especially in patients with an aorto-enteric fistula. A cost-benefit analysis could be useful to evaluate the yield.

Hybrid Repair of an Aneurysm of the Innominate Artery.

INTRODUCTION: Innominate artery aneurysms (IAAs) are rare. They are notorious for causing thromboembolic events. Modern imaging modalities make early detection in an asymptomatic phase possible. In Kieffer group B aneurysms the origin of the innominate artery is affected. Thanks to the combination of open and endovascular techniques, off pump repair is feasible in patients with a fragile aortic arch. During this hybrid procedure the aortic arch is debranched and reinforced with a stent graft. REPORT: A 73 year old white man with a history of extensive thoraco-abdominal aortic reconstructions for aneurysmal disease presented with a progressive Kieffer B IAA of 35 mm. He underwent an off pump hybrid repair. A bifurcated Dacron prosthesis was used for the debranching. The main body originated from the ascending aorta. The right limb was anastomosed to the common ostium of the right carotid and subclavian arteries. The left limb was anastomosed to the left subclavian and carotid artery. The aortic arch was reinforced with a 40 × 162 mm Zenith TX2 endoprosthesis. The endoprosthesis was inserted through a temporary conduit on the main body and deployed during rapid ventricular pacing. The endoprosthesis lined the ascending aorta distal to the debranching up to Ishimaru zone 3. The antegrade insertion prevented excessive manipulation of the aortic arch and the tortuous aorta, which was lined with mural thrombus. Post-operative computed tomography showed a patent debranching with excellent alignment of the endoprosthesis without endoleak. DISCUSSION: Hybrid repair of the aortic arch is well described in literature. This technique was adapted in the treatment of a Kieffer group B IAA. The tortuous aorta and mural thrombus led to the antegrade placement of the endoprosthesis through the main body of the debranched aorta. This approach seems safe and feasible.

Salvage Lobectomy to Treat Necrotizing SARS-CoV-2 Pneumonia Complicated by a Bronchopleural Fistula.

We report a case of necrotizing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia complicated by a bronchopleural fistula and treated by decortication and salvage lobectomy. Owing to the unknown characteristics of the underlying SARS-CoV-2 infection, treatment of the abscess and bronchopleural fistula was delayed. This may have resulted in further deterioration of the patient, with ensuing multiple organ dysfunction. Complications of SARS-CoV-2 pneumonia, such as a bacterial abscess and a bronchopleural fistula, should be treated as if the patient were not infected with SARS-CoV-2.

Interruption or Discontinuation of Tyrosine Kinase Inhibitor Treatment in Chronic Myeloid Leukaemia: A Retrospective Cohort Study (SPARKLE) in Belgium.

OBJECTIVES: To assess interruptions/discontinuations of tyrosine kinase inhibitor (TKI) treatment in Belgian patients with chronic myeloid leukaemia (CML). METHODS: This retrospective study included patients with TKI interruptions/discontinuations of ≥4 continuous weeks (no clinical trial context) between May 2013 and May 2016. Data collection took place between October 2016 and February 2017. RESULTS: All 60 participants (69 interruptions/discontinuations) had chronic-phase CML and 75% had at least a major molecular response (≥MMR) at interruption/discontinuation. Most interruptions/discontinuations occurred while on imatinib (36/69; 49%) and dasatinib (20/69; 29%). Most interruptions/discontinuations occurred due to side effects/intolerance (46/69; 67%); other reasons included a wish to conceive (6/69; 9%) and attempts to achieve treatment-free remission (TFR) (6/69; 9%). Interruptions due to side effects occurred later for imatinib- or dasatinib-treated patients than for those on nilotinib or ponatinib. Treatment was re-initiated in 62% (43/69) of cases. Most interruptions caused by side effects/intolerance were followed by treatment changes. All 4 patients with ≥MR 4.5 at interruption/discontinuation and ≥11-month follow-up who had not restarted treatment maintained the response. CONCLUSION: Although TKIs are used for long-term CML treatment, physicians sometimes recommend interruptions/discontinuations. In this study, interruptions/discontinuations were mainly caused by side effects or intolerance, rather than TFR attempts.

Identification of chronic myeloid leukemia patients treated with imatinib who are potentially eligible for treatment discontinuation by assessing real-life molecular responses on the international scale in a EUTOS-certified lab.

A retrospective study was performed to describe molecular responses (MR) on the international scale (IS) in patients with chronic myeloid leukemia (CML) treated with imatinib in routine clinical practice in Belgium and to identify patients potentially eligible for treatment discontinuation. The analysis included 116 patients with CML in chronic phase at treatment centers sending blood samples for molecular follow-up to a single EUTOS-certified laboratory. IS MR from the last patient visit between October 2014 and April 2015 were retrospectively collected. Most patients (93.1%) had an IS MR corresponding to an optimal response per European LeukemiaNet 2013 guidelines; 53.4% (62/116) of patients were in deep molecular responses ≥MR4.5 at their last visit (mean treatment duration: 91.0 months) among whom 36.2% (42/116) had been receiving imatinib for >5.8 years and 26.7% (31/116) for >8 years (margins of error: 8.74% and 8.05%, respectively). These patients would likely have the highest chance of staying in treatment-free remission (TFR) upon discontinuation, based on published TFR trial data. Although our study only provides a snapshot in time of a patient's last MR reported, without precise information regarding MR duration, the study settings could nevertheless support the feasibility of attempting TFR outside clinical trials in the future.

Short-Term Effect of Two Semi-Occluded Vocal Tract Training Programs on the Vocal Quality of Future Occupational Voice Users: "Resonant Voice Training Using Nasal Consonants" Versus "Straw Phonation".

Purpose: The purpose of this study was to determine the short-term effect of 2 semi-occluded vocal tract training programs, "resonant voice training using nasal consonants" versus "straw phonation," on the vocal quality of vocally healthy future occupational voice users. Method: A multigroup pretest-posttest randomized control group design was used. Thirty healthy speech-language pathology students with a mean age of 19 years (range: 17-22 years) were randomly assigned into a resonant voice training group (practicing resonant exercises across 6 weeks, n = 10), a straw phonation group (practicing straw phonation across 6 weeks, n = 10), or a control group (receiving no voice training, n = 10). A voice assessment protocol consisting of both subjective (questionnaire, participant's self-report, auditory-perceptual evaluation) and objective (maximum performance task, aerodynamic assessment, voice range profile, acoustic analysis, acoustic voice quality index, dysphonia severity index) measurements and determinations was used to evaluate the participants' voice pre- and posttraining. Groups were compared over time using linear mixed models and generalized linear mixed models. Within-group effects of time were determined using post hoc pairwise comparisons. Results: No significant time × group interactions were found for any of the outcome measures, indicating no differences in evolution over time among the 3 groups. Within-group effects of time showed a significant improvement in dysphonia severity index in the resonant voice training group, and a significant improvement in the intensity range in the straw phonation group. Conclusions: Results suggest that the semi-occluded vocal tract training programs using resonant voice training and straw phonation may have a positive impact on the vocal quality and vocal capacities of future occupational voice users. The resonant voice training caused an improved dysphonia severity index, and the straw phonation training caused an expansion of the intensity range in this population.

Intraductal papillary neoplasm of the bile duct: a case report.

Intraductal papillary neoplasm of the bile duct (IPNB) is a rare variant of bile duct tumors, characterized by papillary growth within the bile duct lumen and is regarded as a biliary counterpart of intraductal papillary mucinous neoplasm (IPMN) of the pancreas. IPNBs are mainly found in patients from Far Eastern areas, where hepatolithiasis and clonorchiasis are endemic. The Western experience, however, remains limited. In this article, we report a 56-year-old man, referred to our hospital because of deranged liver function tests. Further imaging modalities showed a cystic lesion of 9 cm diameter, arising from the left hepatic duct. Inlying was a heterogeneous, lobulated mass. The patient underwent a left hemihepatectomy and adjuvant chemotherapy. Despite recent advanced technologies, diagnosis of IPNB is still challenging, especially in western countries due to its rarity. Early identification and resection of lesions, even in asymptomatic or minimally symptomatic patients, are however important prognostic factors.

An unusual presentation of an incarcerated Spigelian hernia.

Spigelian hernias are rare hernias, occurring through a defect in the Spigelian aponeurosis. Like other hernias, they may contain abdominal contents but are more likely to be incarcerated due to the small size of the fascial defect. Multiple intra-abdominal organs have reportedly been found in Spigelian hernias. A search of the literature showed only nine reported cases in which an appendix has been found within a Spigelian hernia. We present a patient with a history of lower abdominal pain since 10 weeks with a large intra-abdominal mass in the right iliac fossa. Due to abscess formation with spontaneous evacuation through the abdominal wall, drainage and incision were performed and the patient was treated with broad-spectrum antibiotics. An explorative laparoscopy after six weeks showed an incarcerated appendix in a Spigelian hernia.

Early complications after stapled hemorrhoidopexy: a retrospective study comparing three different circular staplers.

BACKGROUND: A retrospective analysis was performed to assess differences between three devices used for stapled hemorrhoidopexy (SH) in terms of early complications and complaints and the volume of excised tissue. MATERIALS AND METHODS: All patients who underwent an elective SH from January 2008 to December 2014 were included. Three different devices were used: the PPH03 stapler (Ethicon EndoSurgery, Diegem, Belgium) and the ChexTM CPH32 and CPH34 staplers (Frankenman International Ltd, Hong Kong, China). The demographic data were reviewed as well as indications for surgery. The volume of the excised tissue was determined by reviewing the anatomopathologic reports. We assessed early postoperative complications and complaints and compared the rate of complications between the three used devices. RESULTS: From 1 January 2008 to 30 December 2014, 253 patients underwent a SH using three different devices. One hundred and seventy-four patients were treated with the PPH03 stapler, 51 with the ChexTM CPH32 stapler and 28 with the ChexTM CPH34 stapler. Postoperatively, 28.5% of patients experienced minor early complications. There was no difference in complication rates between the three different devices, except for the occurrence of postoperative stenosis with more stricture formation when using the CPH32 stapler (p < 0.0001). The volume of tissue excised by the ChexTM CPH32 and CPH34 staplers was significantly larger than in the PPH03 group (18.19 ± 9.67 mL; 25.53 ± 13.99 mL; 11.63 ± 5.66 mL; p < 0.0001). CONCLUSIONS: Postoperative anal stenosis was more common after circular stapled hemorrhoidopexy with the ChexTM CPH32 stapler.

Hemodialysis access-induced ischemia is not related to configuration and access flow rates of upper arm arteriovenous fistulas at the elbow.

BACKGROUND: The purpose of the study was to find a relationship between the configuration of autogenous upper arm arteriovenous fistulas (AVFs) at the elbow and high access flow rates. METHODS: Forty-seven patients with well-functioning autogenous upper arm AVFs at the elbow were included. The configuration of the AVF and access flow rate was determined by duplex scanning. RESULTS: Hemodialysis access-induced distal ischemia scores and access flow rates were comparable in AVFs with 1 or 2 efferent veins (1829.9 ± 1121.3 mL/min, range [400-5000] vs. 1988.5 ± 1324.5 mL/min, range [130-5000]; P = 0.61). The basilic vein had statistically significant larger diameters than the cephalic vein (8.1 ± 2.7 mm, range [2.7-11.0] vs. 5.8 ± 2.5 mm, range [3.8-13.0]; P = 0.02), but no statistically significant difference in flow rates were observed (1884.5 ± 889.0 mL/min, range [824-3600] vs. 1130.0 ± 1258.4 mL/min, range [400-5000]; P = 0.53). Access flow rates were higher in AVFs with the brachial artery as afferent artery than when the radial artery was used (1909.5 ± 1273.2 mL/min, range [550-5000] vs. 1188.6 ± 642.7 mL/min, range [130-2800]; P = 0.02). CONCLUSIONS: There is no difference in access flow rates in autogenous AVFs at the elbow with 1 or 2 efferent veins. Autogenous AVFs at the elbow on the radial artery have lower access flow rates than AVFs on the brachial artery.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) impairs the regulation of apoptosis in megakaryocytes by activating NF-κB: a proteomic study.

We previously showed that the Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and its receptor VPAC1 are negative regulators of megakaryopoiesis and platelet function, but their downstream signaling pathway that inhibits this process still remained unknown. A combined proteomic, transcriptomic, and bioinformatic approach was here used to elucidate the molecular mechanisms underlying PACAP signaling via VPAC1 in megakaryocytes. Two-dimensional difference gel electrophoresis and tandem MS were applied to detect differentially expressed proteins in megakaryocytic CHRF cells stimulated with PACAP. The majority of the 120 proteins modulated by PACAP belong to the class of "cell cycle and apoptosis" proteins. The up- or down-regulated expression of some proteins was confirmed by immunoblot and immunohistochemical analysis. A meta-analysis of our data and 12 other published studies was performed to evaluate signaling pathways involved in different cellular models of PACAP response. From 2384 differentially expressed genes/proteins, 83 were modulated by PACAP in at least three independent studies and Ingenuity Pathway Analysis further identified apoptosis as the highest scored network with NF-κB as a key-player. PACAP inhibited serum depletion-induced apoptosis of CHRF cells via VPAC1 stimulation. In addition, PACAP switched on NF-κB dependent gene expression since higher nuclear levels of the active NF-κB p50/p65 heterodimer were found in CHRF cells treated with PACAP. Finally, a quantitative real time PCR apoptosis array was used to study RNA from in vitro differentiated megakaryocytes from a PACAP overexpressing patient, leading to the identification of 15 apoptotic genes with a 4-fold change in expression and Ingenuity Pathway Analysis again revealed NF-κB as the central player. In conclusion, our findings suggest that PACAP interferes with the regulation of apoptosis in megakaryocytes, probably via stimulation of the NF-κB pathway.

Role of p-glycoprotein expression and function in cystinotic renal proximal tubular cells.

P-glycoprotein (P-gp) is an ATP-dependent transporter localized at the apical membrane of the kidney proximal tubules, which plays a role in the efflux of cationic and amphipathic endogenous waste products and xenobiotics, such as drugs, into urine. Studies in mice deficient in P-gp showed generalized proximal tubular dysfunction similar to the phenotype of patients with cystinosis, an autosomal recessive disorder caused by mutations in the lysosomal cystine transporter cystinosin. Renal disease in cystinosis is characterized by generalized dysfunction of the apical proximal tubular influx transporters (so-called renal Fanconi syndrome) developing during infancy and gradually progressing towards end-stage renal disease before the 10th birthday in the majority of patients that are not treated with the cystine-depleting drug cysteamine. Here, we investigated whether the proximal tubular efflux transporter P-gp is affected in cystinosis and whether this might contribute to the development of renal Fanconi syndrome. We used conditionally immortalized (ci) proximal tubular epithelial cells (ciPTEC) derived from cystinotic patients and healthy volunteers. P-gp-mediated transport was measured by using the P-gp substrate calcein-AM in the presence and absence of the P-gp-inhibitor PSC833. P-gp activity was normal in cystinotic cells as compared to controls. Additionally, the effect of cysteamine on P-gp transport activity and phosphate uptake was determined; demonstrating increased P-gp activity in cystinotic cells, and further decrease of proximal tubular phosphate uptake. This observation is compatible with the persistence of renal Fanconi syndrome in vivo under cysteamine therapy. In summary, P-gp expression and activity are normal in cystinotic ciPTEC, indicating that P-gp dysfunction is not involved in the pathogenesis of cystinosis.

Thrombopoietic effect of VPAC1 inhibition during megakaryopoiesis.

Megakaryocytes and platelets express the stimulatory G protein (Gs)-coupled VPAC1 receptor, for which the pituitary adenylyl cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) are agonists. The neuropeptide PACAP and VPAC1 were previously found to negatively regulate megakaryopoiesis, and inhibition of their physiological pathway was found to have a thrombopoietic effect in conditions where megakaryopoiesis and thrombopoiesis were impaired, such as chemotherapy-induced thrombocytopenia and congenital thrombocytopenia. The present study explored the thrombopoietic effect of VPAC1 inhibition in a murine model of syngeneic bone marrow transplantation (BMT) and in passive immune thrombocytopenia. Treatment of donor mice with a neutralizing anti-VPAC1 antibody stimulated the initial, most critical recovery of the platelets in irradiated mice. In the passive immune thrombocytopenia model, we observed a thrombopoietic effect, resulting in a less severe platelet drop after induction of their removal in the spleen by an anti-platelet antibody. We concluded that inhibition of the physiological PACAP/VPAC1 pathway could stimulate in vivo megakaryopoiesis. This inhibition can be applied to attenuate thrombocytopenia in conditions where platelets are destroyed as the major pathogenetic mechanism, e.g. immune thrombocytopenia purpura, or need to be produced de novo, e.g. after irradiation and BMT.

Emerging treatments for thrombocytopenia: increasing platelet production.

Thrombocytopenia is a common medical problem. The first generation thrombopoietic agents, recombinant THPO and 'megakaryocyte growth and development factor' (PEG-rHuMGDF) entered clinical trials, but their development was discontinued owing to neutralizing auto-antibodies cross-reacting with endogenous THPO, causing thrombocytopenia in healthy volunteers. Although an approved drug for prevention of severe thrombocytopenia following myelosuppressive chemotherapy (human Interleukin-11) exists, the search for new thrombopoietic agents continued because its use is limited by side effects. Several second generation thrombopoietic factors have entered clinical trials and some new negative regulators of megakaryopoiesis have been found, such as platelet factor 4 (PF4) and the pituitary adenylate cyclase activating polypeptide (PACAP). Their inhibition may be useful in the treatment of thrombocytopenia. This article reviews second generation thrombopoietic factors and those recently discovered regulators of megakaryopoiesis.

PACAP and its receptor VPAC1 regulate megakaryocyte maturation: therapeutic implications.

Megakaryocytes and platelets express the Gs-coupled VPAC1 receptor, for which the pituitary adenylyl cyclase-activating peptide (PACAP) and the vasointestinal peptide (VIP) are agonists. We here demonstrate a regulatory role for VPAC1 signaling during megakaryopoiesis. A total of 2 patients with trisomy 18p with PACAP overexpression and transgenic mice overexpressing PACAP in megakaryocytes have thrombopathy, a mild thrombocytopenia, and a reduced number of mature megakaryocytes in their bone marrow. In vitro differentiation of hematopoietic stem cells from the patient and transgenic mice shows a reduced number of megakaryocyte colonies compared with controls. The addition of PACAP, VIP, or the adenylyl cyclase activator forskolin to CD34(+) cells inhibits megakaryocyte differentiation. In contrast, neutralizing monoclonal anti-PACAP (PP1A4) or anti-VPAC1 (23A11) antibodies inhibit cAMP formation and stimulate megakaryopoiesis in a thrombopoietin-independent manner. Moreover, wild-type mice obtain an increased platelet count after subcutaneous injection of PP1A4 or 23A11. These antibodies also elevate platelet numbers in animal models of myelosuppressive therapy and in GATA1-deficient mice with congenital thrombocytopenia. Furthermore, 23A11 stimulates the in vitro megakaryocyte differentiation of both normal and GATA1-deficient human CD34(+) cells. Together, our data strongly suggest that VPAC1 signaling tempers normal megakaryopoiesis, and that inhibition of this pathway stimulates megakaryocyte differentiation, enhancing platelet recovery after myelosuppressive therapy and in GATA1 deficiency.