Longitudinal outcomes of COVID-19 in solid organ transplant recipients from 2020 to 2023.

Data regarding coronavirus disease 2019 (COVID-19) outcomes in solid organ transplant recipients (SOTr) across severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) waves, including the impact of different measures, are lacking. This cohort study, conducted from March 2020 to May 2023 in Toronto, Canada, aimed to analyze COVID-19 outcomes in 1975 SOTr across various SARS-CoV-2 waves and assess the impact of preventive and treatment measures. The primary outcome was severe COVID-19, defined as requiring supplemental oxygen, with secondary outcomes including hospitalization, length of stay, intensive care unit (ICU) admission, and 30-day and 1-year all-cause mortality. SARS-CoV-2 waves were categorized as Wildtype/Alpha/Delta (318 cases, 16.1%), Omicron BA.1 (268, 26.2%), Omicron BA.2 (268, 13.6%), Omicron BA.5 (561, 28.4%), Omicron BQ.1.1 (188, 9.5%), and Omicron XBB.1.5 (123, 6.2%). Severe COVID-19 rate was highest during the Wildtype/Alpha/Delta wave (44.6%), and lower in Omicron waves (5.7%-16.1%). Lung transplantation was associated with severe COVID-19 (OR: 4.62, 95% CI: 2.71-7.89), along with rituximab treatment (OR: 4.24, 95% CI: 1.04-17.3), long-term corticosteroid use (OR: 3.11, 95% CI: 1.46-6.62), older age (OR: 1.51, 95% CI: 1.30-1.76), chronic lung disease (OR: 2.11, 95% CI: 1.36-3.30), chronic kidney disease (OR: 2.18, 95% CI: 1.17-4.07), and diabetes (OR: 1.97, 95% CI: 1.37-2.83). Early treatment and ≥3 vaccine doses were associated with reduced severity (OR: 0.29, 95% CI: 0.19-0.46, and 0.35, 95% CI: 0.21-0.60, respectively). Tixagevimab/cilgavimab and bivalent boosters did not show a significant impact. The study concludes that COVID-19 severity decreased across different variants in SOTr. Lung transplantation was associated with worse outcomes and may benefit more from preventive and early therapeutic interventions.

COVID-19 Reinfection Has Better Outcomes Than the First Infection in Solid Organ Transplant Recipients.

BACKGROUND: Solid organ transplant recipients face an increased risk of severe coronavirus disease 2019 (COVID-19) and are vulnerable to repeat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. In nonimmunocompromised individuals, SARS-CoV-2 reinfections are milder likely because of cross-protective immunity. We sought to determine whether SARS-CoV-2 reinfection exhibits milder manifestations than primary infection in transplant recipients. METHODS: Using a large, prospective cohort of adult transplant patients with COVID-19, we identified patients with SARS-CoV-2 reinfections. We performed a 1:1 nearest neighbor propensity score matching to control potential confounders, including the COVID-19 variant. We compared outcomes including oxygen requirement, hospitalization, and intensive care unit admission within 30 d after diagnosis between patients with reinfection and those with the first episode of COVID-19. RESULTS: Between 2020 and 2023, 103 reinfections were identified in a cohort of 1869 transplant recipients infected with SARS-CoV-2 (incidence of 2.7% per year). These included 50 kidney (48.5%), 27 lung (26.2%), 7 heart (6.8%), 6 liver (5.8%), and 13 multiorgan (12.6%) transplants. The median age was 54.5 y (interquartile range [IQR], 40.5-65.5) and the median time from transplant to first infection was 6.6 y (IQR, 2.8-11.2). The time between the primary COVID-19 and reinfection was 326 d (IQR, 226-434). Three doses or more of SARS-CoV-2 vaccine are received by 87.4% of patients. After propensity score matching, reinfections were associated with significantly lower hospitalization (5.8% versus 19.4%; risk ratio, 0.3; 95% CI, 0.12-0.71) and oxygen requirement (3.9% versus 13.6%; risk ratio, 0.29; 95% CI, 0.10-0.84). In a within-patient analysis only in the reinfection group, the second infection was milder than the first (3.9% required oxygen versus 19.4%, P < 0.0001), and severe first COVID-19 was the only predictor of severe reinfection. CONCLUSIONS: Transplant recipients with COVID-19 reinfection present better outcomes than those with the first infection, providing clinical evidence for the development of cross-protective immunity.

Short-course early outpatient remdesivir prevents severe disease due to COVID-19 in organ transplant recipients during the omicron BA.2 wave.

Solid organ transplant recipients (SOTr) remain at risk of severe COVID-19. Several previous early therapies are no longer effective against new circulating variants. We performed a prospective cohort study in outpatient adult SOTr during the omicron BA.2 wave (April-May 2022), to determine the effectiveness of 3 doses of remdesivir given within 7 days of symptoms onset. Patients were followed for at least 30 days. The primary outcome was hospitalization. Of 210 SOTr that had COVID-19, we included 192. The median age was 54.5 years and 61.5% were men. The most common transplants were kidney (41.7%), lung (19.3%), liver (18.8%), and heart (6.3%). Most patients (90.1%) had previously received ≥3 COVID-19 vaccine doses. Fifteen (7.8%) were hospitalized, 5(2.6%) required supplemental oxygen, 3(1.6%) ICU admission, and 2(1%) mechanical ventilation with 2(1%) deaths. Age, the number of comorbidities, prednisone chronic treatment, and lung transplant were risk factors for hospitalization. Early remdesivir significantly decreased the hospitalization rate: adjusted hazard ratio 0.12 (95% CI: 0.03-0.57). The adjusted number needed to treat to prevent one hospitalization was 15.2 (95% CI: 13.6-31.4). No patient that received early remdesivir needed ICU admission or died. In a cohort of SOTr with COVID-19 infection, administration of 3-dose early remdesivir independently reduced the disease severity.

Homotypic and heterotypic immune responses to Omicron variant in immunocompromised patients in diverse clinical settings.

Immunocompromised patients are predisposed to severe COVID-19. Here we compare homotypic and heterotypic humoral and cellular immune responses to Omicron BA.1 in organ transplant patients across a diverse clinical spectrum. We perform variant-specific pseudovirus neutralization assays for D614G, and Omicron-BA.1, -BA.2, and Delta variants. We also measure poly-and monofunctional T-cell responses to BA.1 and ancestral SARS-CoV-2 peptide pools. We identify that partially or fully-vaccinated transplant recipients after infection with Omicron BA.1 have the greatest BA.1 neutralizing antibody and BA.1-specific polyfunctional CD4+ and CD8+ T-cell responses, with potent cross-neutralization against BA.2. In these patients, the magnitude of the BA.1-directed response is comparable to immunocompetent triple-vaccinated controls. A subset of patients with pre-Omicron infection have heterotypic responses to BA.1 and BA.2, whereas uninfected transplant patients with three doses of vaccine demonstrate the weakest comparative responses. These results have implications for risk of infection, re-infection, and disease severity among immune compromised hosts with Omicron infection.

Impact of Vaccination and Early Monoclonal Antibody Therapy on Coronavirus Disease 2019 Outcomes in Organ Transplant Recipients During the Omicron Wave.

BACKGROUND: Solid organ transplant (SOT) recipients are at high risk for complications from coronavirus disease 2019 (COVID-19) and vaccine breakthrough infections are common. We determined the effectiveness of ≥3 doses of mRNA vaccine and early monoclonal antibody therapy in reducing disease severity against the Omicron (B.1.1.529) variant. METHODS: Prospective cohort study of consecutive SOT recipients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection referred to our transplant center who were followed for at least 30 days. The primary outcome was supplemental oxygen requirement. Effectiveness of sotrovimab and ≥3 vaccine doses was estimated using adjusted risk ratios (RR). RESULTS: Three hundred adult organ transplant recipients were included. Seventy-one patients (24.1%) were hospitalized, 44 (14.9%) required supplemental oxygen, 19 (6.5%) were admitted to the intensive care unit (ICU), 15 (5.1%) required mechanical ventilation (MV), and 13 (4.4%) died. On multivariate analysis, age and multiple comorbidities were risk factors for oxygen requirement. Both receipt of ≥3 vaccine doses prior to SARS-CoV-2 infection and receipt of sotrovimab in the first 7 days of symptom onset was associated with a reduction in the need for supplemental oxygen (RR 0.30 [95% confidence interval {CI}: .17 to .54] and RR 0.24 (95% CI: .1 to .59), respectively]. For sotrovimab, the number needed to treat (NNT) to prevent one patient requiring oxygen was 6.64 (95% CI: 4.56-13.66). Both sotrovimab use and having received ≥3 vaccine doses were also associated with a shorter hospitalization length of stay. CONCLUSIONS: In a cohort of SOT recipients with Omicron variant COVID-19 infection, prior receipt of ≥3 mRNA vaccine doses and early monoclonal antibody therapy were independently associated with significantly reduced disease severity.

AMF communities associated to Vitis vinifera in an Italian vineyard subjected to integrated pest management at two different phenological stages.

Vitis vinifera L. is an economically important crop that can be influenced by soil microorganisms, including arbuscular mycorrhizal fungi (AMF), that establish symbiotic associations with its roots. AMF have beneficial effects on grapevine performance improving water use efficiency and replant success. Most grapevine varieties are susceptible to various diseases, and integrated pest management (IPM) is one of the emerging approaches to perform pest control. In the present study, we examined the AMF communities present in the soil associated to the roots of V. vinifera cv. Pinot Noir (comparing them to those present in a soil not affected by grapevine roots), in a vineyard subjected to IPM at two different phenological stages, using 454 Roche sequencing technology. We proposed a new approach to analyze sequencing data. Most of the taxa were included in the family Glomeraceae. In particular, Glomus sp. Rhizophagus sp. and Septoglomus viscosum were present. The family Archeosporaceae was represented only by the genus Archeospora sp. Different AMF communities were found in the two soils and the importance of the phenological stage in regulating AMF biodiversity was assessed.

Transient paraplegia due to subarachnoid haemorrhage following spinal anaesthesia.

Spinal subarachnoid haemorrhage is a rare complication of spinal anaesthesia, especially following atraumatic lumbar puncture and in the absence of coagulopathies. The initial presentation of spinal subarachnoid haemorrhage is variable and paraplegia with full recovery within a few hours is rare. Bleeding can extend into the intracranial subarachnoid space, but there are only a few reports of symptomatic intracranial and spinal subarachnoid haemorrhage after spinal anaesthesia. We report co-existing spinal subarachnoid haemorrhage and intracranial subarachnoid haemorrhage after atraumatic spinal anaesthesia in a 69-year-old woman without a coagulopathy. The day after surgery she developed flaccid paraplegia that spontaneously resolved in a few hours. Magnetic resonance imaging demonstrated subarachnoid high signal intensity from T11-S2, consistent with spinal subarachnoid haemorrhage. On the same day the patient complained of severe headache which was later followed by diplopia. Neurological imaging studies revealed diffuse distribution of blood in the subarachnoid space but no intracranial vascular malformations. At the time of diagnosis spontaneous recovery of spinal symptoms had already begun and the clinical manifestations eventually resolved with conservative management. The possibility of an intracranial haemorrhage should always be considered when spinal subarachnoid haemorrhage is identified, even in cases of uncomplicated spinal anaesthesia in patients with no known risk factors for spinal haemorrhage.

Oncological outcomes of parotid gland malignancies: a retrospective analysis of 74 patients.

INTRODUCTION: Salivary gland malignancies are rare neoplasms whose management has been evolving over the last two decades. Nevertheless, patient outcomes have not improved accordingly. OBJECTIVE: In the present paper, factors and variables that could influence Overall, Disease-Specific and Disease-Free Survival, and Loco-Regional Control were analyzed. METHODS: Chart data from 74 patients who underwent parotid gland surgery were retrospectively analyzed and stratified for tumor histology, grading, size, pT stage, pN stage, extracapsular spread, involved salivary gland lobe, and age at diagnosis. Major outcomes were estimated at 5 years by Kaplan-Meier curves. RESULTS: Advanced stage, high grade, and lymph nodes involvement greatly impaired patient outcomes. Furthermore, in our cohort, the age at diagnosis ≥ 55 was a cause of poorer disease survival likely due to a different distribution in tumor histotypes between older and younger patients. Despite the two groups were homogeneous for the numerosity of squamous cell carcinomas, older patients were more rarely affected by mucoepidermoid and acinic cell carcinomas, which have generally better prognosis. Finally, patients aged ≥ 55 had a more frequent pathological involvement of the deep lobe of the parotid gland if compared to the younger counterpart. CONCLUSION: The rarity of some salivary gland tumor histotypes requires further high-number series to fully understand the prognostic factors for both patient survival and recurrence development. In our cohort, the age at diagnosis ≥ 55 raises concerns that play crucial roles in disease survival shortening.

Metaproteomic characterization of theVitis vinifera rhizosphere.

The rhizosphere is a hotspot of microbial activity where the release of root exudates stimulates bacterial density and diversity. The majority of the bacterial cells in soil are viable, unculturable, but active. Proteomic tools could be useful in gaining information about microbial community activity and to better understand the real interactions between roots and soil. The aim of this work was to characterize the bacterial community associated with Vitis vinifera cv. Pinot Noir roots using a metaproteome approach. Our results confirmed the large potential of proteomics in describing the environmental microbial communities and their activities: in particular, we showed that bacteria belonging to Streptomyces, Bacillus, Bradyrhizobium, Burkholderia and Pseudomonas genera are the most active in protein expression. Concerning the biological activity of these genera in the rhizosphere, we observed the exclusive presence of the phosphorus metabolic process and the regulation of primary metabolic processes. To our knowledge, this is the first study reporting the rhizosphere proteome of V. vinifera, describing the bacterial community structure and activity of an important ecosystem for the Italian landscape, agriculture and economy.

Antifungal activity of essential oils against azole-resistant and azole-susceptible vaginal Candida glabrata strains.

Candida glabrata is an opportunistic pathogen, associated with endocarditis, meningitis, and disseminated disease, and also with complicated vaginitis. Essential oils derived from aromatic plants are known in traditional medicine as antimicrobial agents and have antifungal properties. The aim of this work was to evaluate whether 12 tested essential oils (tea tree, laurel, anise, basil, bergamot, lavender, mint, oregano, grapefruit, rosemary, winter savory, and ginger) could have a transverse effect on C. glabrata sensitive strains but above all on strains resistant to the three main azole antifungals used (clotrimazole, fluconazole, itraconazole). For this reason, different strains of C. glabrata, vaginal isolated, were characterized (disk diffusion assay, minimal inhibitory concentration) with respect to their response to such antifungals. Electron microscopy analyses were performed to examine cellular damages in depth. Subsequently, we wanted to evaluate the effect of the oils on human cells to estimate their potential cytotoxicity. Oregano and winter savory were the two most effective essential oils, inducing growth inhibition, cell damage of C. glabrata strains (both sensitive and resistant to azole antifungal drugs), and medium-high level of toxicity against human keratinocytes. The results of this work support the research for new alternatives or complementary therapies against vaginal candidiasis.

Unravelling the risk factors that underlie oral and oropharyngeal surgery in elderly.

Oral squamous cell carcinoma (OSCC) diagnoses in elderly patients are expected to double in the next 20 years. Current guidelines suggest surgery as a preferred approach, but elderly patients are hardly considered suitable to challenging surgical treatments. Using a multi-centric retrospective analysis, we evaluated the outcomes of 99 patients affected by OSCC and aged at least 70, who underwent to either transoral procedures (TP), open neck resection without (OR) or with reconstruction (ORR). In our cohort, overall survival was significantly hampered by concomitant diseases and postsurgical complications, whose development is driven by the former. Thus, our findings support the growing acceptance that chronological age alone should not be a sufficient contraindication for aggressive surgery in the treatment of OSCC. However, elderly patients affected by OSCC are undoubtedly delicate surgical candidates and accurate selection prior to surgery with curative intent is mandatory.

Subcutaneous Achilles tendon rupture: A comparison between open technique and mini-invasive tenorrhaphy with Achillon® suture system.

BACKGROUND: Surgical management of Achilles tendon rupture is still controversial: open techniques have a higher rate of soft tissue complications but a lower incidence of re-rupture than percutaneous tenorrhaphies. The aim of our retrospective study was to analyze and compare clinical and functional results in patients treated with either the conventional open or minimally invasive suture treatment with the Achillon® system. METHODS: A retrospective review of 140 patients was performed; 72 were treated with open tenorrhaphy, 68 with the minimally invasive Achillon® suture system. RESULTS: With a comparable re-rupture rate, there was a statistically significant reduction in surgical time, incidence of minor complications, time required to return to sport activities and return to work in the minimally invasive group. CONCLUSIONS: Achillon® mini-invasive suture system is a reliable tool for the Achilles tendon ruptures, able to reduce the incidence of soft tissues complications if compared to the classic open tenorrhaphy, while maintaining strength of the suture and leading to superimposed functional outcomes.

Sensitivity of Candida albicans to essential oils: are they an alternative to antifungal agents?

AIMS: Candida albicans is an important opportunistic pathogen, responsible for the majority of yeast infections in humans. Essential oils, extracted from aromatic plants, are well-known antimicrobial agents, characterized by a broad spectrum of activities, including antifungal properties. The aim of this work was to assess the sensitivity of 30 different vaginal isolated strains of C. albicans to 12 essential oils, compared to the three main used drugs (clotrimazole, fluconazole and itraconazole). METHODS AND RESULTS: Thirty strains of C. albicans were isolated from vaginal swab on CHROMagar™ Candida. The agar disc diffusion method was employed to determine the sensitivity to the essential oils. The antifungal activity of the essential oils and antifungal drugs (clotrimazole, itraconazole and fluconazole) were investigated using a microdilution method. Transmission and scanning electron microscopy analyses were performed to get a deep inside on cellular damages. Mint, basil, lavender, tea tree oil, winter savory and oregano essential oils inhibited both the growth and the activity of C. albicans more efficiently than clotrimazole. Damages induced by essential oils at the cellular level were stronger than those caused by clotrimazole. CONCLUSIONS: Candida albicans is more sensitive to different essential oils compared to the main used drugs. Moreover, the essential oil affected mainly the cell wall and the membranes of the yeast. SIGNIFICANCE AND IMPACT OF THE STUDY: The results of this work support the research for new alternatives or complementary therapies against vaginal candidiasis.

Unravelling the risk factors that underlie laryngeal surgery in elderly.

Older patients are not considered good candidates to undergo more challenging therapeutic treatments, e.g. highly invasive surgery and complex chemotherapy. However, their exclusion from standard therapeutic options is not justifiable. Herein, we reviewed 212 patients aged ≥ 70, affected with laryngeal squamous cell carcinoma, and treated with transoral laser microsurgery or open neck (partial / total) laryngectomy with radical intent. The main aim was to compare patient outcomes to identify predictive factors that can be used by surgeons to choose the most appropriate treatment option. In our cohort, patients affected with more advanced tumour and hence treated by invasive open neck surgeries (above all TL) are more prone to develop complications and undergo fatal outcome than those with early disease treated by laser microsurgery, independently of age at surgery. In conclusion, elderly patients affected by laryngeal cancer can be treated similarly to younger patients, keeping in mind that more invasive surgeries are associated with a higher risk of developing complications. The advantages of mini-invasive surgery make it a possible first choice treatment in very old and frail patients suffering from laryngeal cancer, especially considering the recent success in treatment of some advanced stage tumours. Furthermore, comorbidities, by themselves, should not be used as exclusion criteria for subjecting an elderly patient to a different treatment that is from standard therapy.

Supratracheal laryngectomy: current indications and contraindications.

Cancer of the larynx in the intermediate/advanced stage still presents a major challenge in terms of controlling the disease and preserving the organ. Supratracheal partial laryngectomy (STPL) has been described as a function-sparing surgical procedure for laryngeal cancer with sub-glottic extension. The aim of the present multi-institutional study was to focus on the indications and contraindications, both local and general, for this type of surgery based on the long-term oncological and functional results. We analysed the clinical outcomes of 142 patients with laryngeal cancer staged pT2-pT4a who underwent STPL. Five-year overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS) and loco-regional control (LRC) rates were: glottic pT2 [71.4%, 95.2%, 76.0%, 76.0%], glottic-transglottic pT3 [85.3%, 91.1%, 86.4%, 88.7%], and pT4a [73.2%, 88.1%, 52.7%, 60.7%], respectively. DFS and LRC prevalences at 5 years were greatly affected by pT4a staging. Five-year laryngeal function preservation (LFP) and laryngectomy free survival (LFS) were: glottic pT2 [90.9%, 95.2%], glottic-transglottic pT3 [84.4%, 93.1%], and pT4a [63.7%, 75.5%], respectively, being affected by pT staging and age 65 ≥ years (LFP 54.1%). As a result of Type III open horizontal partial laryngectomies (OPHLs) (supratracheal laryngectomies), the typical subsites of local failure inside the larynx were the mucosa at the passage between the remnant larynx and trachea, the mucosa at the level of the posterior commissure and the contralateral cricoarytenoid unit as well as outside the larynx at the level of the outer surface of the remnant larynx. For patients with glottic or transglottic tumours and with sub-glottic extension, the choice of STPL can be considered to be effective, not only in prognostic terms, but also in terms of functional results.

Alpha-linolenic acid protects against cardiac injury and remodelling induced by beta-adrenergic overstimulation.

We investigated the effect of α-linolenic acid (ALA) in protecting the heart from injury caused by ß-adrenergic overstimulation. ALA's role either in isoproterenol (ISO)-treated isolated rat cardiomyocytes (H9c2 cells) or in in vivo rat hearts was studied. In isolated cardiomyocytes in vitro, the involvement of kinases (Src and PI3K) in protection was tested using the specific inhibitors (PP2 or LY294002 respectively), while the role of caveolae was assessed by their disruption with methyl-ß-cyclodextrin. The rats underwent either a normal chow diet or, alternatively, an ALA-enriched diet before, during and throughout the 60 days after 5 days of isoproterenol administration. Before sacrifice, the hemodynamic changes were measured using echocardiography. In the explanted hearts, histological changes together with molecular markers of cardiac fibrosis and hypertrophy were evaluated. In H9c2 cells, ALA abolished the ISO-induced reduction of viability. This effect was suppressed by both the inhibitor PP2 or LY294002 and the caveolae disrupter methyl-ß-cyclodextrin. In the rats, ALA prevented ISO-induced myocardial fibrosis and hypertrophy and kept the cardiac mechanical function as in the control. It also counteracted the increased expressions of transforming growth factor-ß (TGF-ß) and ß-myosin (ß-MHC), the decreased expression of tissue inhibitor metalloproteinase-1 (TIMP-1) and the enhanced activity of matrix metalloproteinase-2 (MMP-2). In conclusion, ALA-induced protection requires the integrity of caveolae where ß2-adrenergic receptors (ß2ARs) are restricted and mediate the activation of the Src-PI3K protective pathway. By preserving this ß2AR pro-survival pathway, an ALA-enriched diet protects the heart against ISO-induced fibrosis and hypertrophy.

Injured cardiomyocytes promote dental pulp mesenchymal stem cell homing.

BACKGROUND: The heart is unable to regenerate its tissues after severe injuries. Stem cell therapy appears to be one of the most promising approaches, though preclinical results are hitherto contradictory and clinical trials scanty and/or limited to phase-I. The limited knowledge about stem cell early homing in infarcted cardiac tissues can concur to this scenario. METHODS: The stem cell migration was assessed in in-vitro and ex-vivo models of heart ischemia, employing a rat dental pulp stem cell line (MUR-1) that shares the same ontogenic progenitors with portions of the heart, expresses markers typical of cardiac/vascular-like progenitors and is able to differentiate into cardiomyocytes in-vitro. RESULTS: Here, we demonstrated that the MUR-1 can reach the injured cells/tissue and make contacts with the damaged cardiomyocytes, likely through Connexin 43, N-cadherin and von Willebrand Factor mediated cell-cell interactions, both in in-vitro and ex-vivo models. Furthermore, we found that SDF-1, FGF-2 and HGF, but not VEGF are involved as chemotactic factors in MUR-1 migration, notifying a similarity with neural crest cell behavior during the organogenesis of both the splanchnocranium and the heart. CONCLUSIONS: Herein we found a similarity between what happens during the heart organogenesis and the early migration and homing of MUR-1 cells in ischemic models. GENERAL SIGNIFICANCE: The comprehension of molecular aspects underlying the early phases of stem cell migration and interaction with damaged organ contributes to the future achievement of the coveted stem cell-mediated organ regeneration and function preservation in-vivo.