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The development of immune checkpoint inhibitor (ICI) immunotherapy has revolutionized the treatment of several cancers. Malignancies are one of the leading causes of death in solid organ transplant recipients (SOTRs). Although ICI treatment may be an effective option in treating malignancies in SOTRs, concerns about triggering allograft rejection have been raised in this population. Herein, we will review currently available data regarding patients, allograft and malignancy outcomes in SOTRs who received ICI therapy.Cancer incidence is three to five-fold higher among SOTRs, compared with the general population. Skin cancer is the most prevalent cancer after transplant, followed by kidney cancer, lymphoma and Kaposi sarcoma. There are no large prospective studies evaluating ICI therapy's use for treating cancers in SOTRs. However, retrospective studies have shown that ICI treatment may be associated with improved malignancy outcomes and overall survival (OS). However, the risk of allograft rejection is high (around 40%) of whom about half lose their allograft. Maintaining higher levels of immunosuppression may be associated with a lower risk of allograft rejection, but potentially worse malignancy outcomes.Although ICI treatment may be associated with improved patient and malignancy outcomes, the risk of allograft rejection and loss are high. Prospective studies are needed to confirm the benefits of ICI therapy in SOTRs and to evaluate the optimal immunosuppression regimen modifications, if any, to improve patient, malignancy and allograft outcomes in transplant recipients.

Antibody-mediated rejection (AMR) has emerged as the leading cause of late graft loss in kidney transplant recipients. Donor-specific antibodies are an independent risk factor for AMR and graft loss. However, not all donor-specific antibodies are pathogenic. AMR treatment is heterogeneous due to the lack of robust trials to support clinical decisions. This review provides an overview and comments on practical but relevant dilemmas physicians experience in managing kidney transplant recipients with AMR.Active AMR with donor-specific antibodies may be treated with plasmapheresis, intravenous immunoglobulin and corticosteroids with additional therapies considered on a case-by-case basis. On the contrary, no treatment has been shown to be effective against chronic active AMR. Various biomarkers and prediction models to assess the individual risk of graft failure and response to rejection treatment show promise.The ability to personalize management for a given kidney transplant recipient and identify treatments that will improve their long-term outcome remains a critical unmet need. Earlier identification of AMR with noninvasive biomarkers and prediction models to assess the individual risk of graft failure should be considered. Enrolling patients with AMR in clinical trials to assess novel therapeutic agents is highly encouraged.

Bone disease after kidney transplantation is associated with an increased risk of fractures, morbidity, and mortality. Its pathophysiology is complex, involving multiple contributors including pretransplant bone disease, immunosuppressive medications, and changes in the parathyroid-bone-kidney axis. Risk scores, bone turnover markers, and noninvasive imaging modalities are only able to partially predict the fracture risk in kidney transplant recipients. The optimal management of bone disease after kidney transplantation has not yet been established, with only a limited number of randomized clinical trials evaluating the efficacy of treatment regimens in kidney transplant recipients. This review focuses on the pathophysiology, evaluation, prevention, and treatment of post-kidney transplant mineral and bone disease as guided by recent evidence.

The neutralizing monoclonal antibody combination of tixagevimab/cilgavimab has been shown to reduce the risk of SARS-CoV-2 infection in unvaccinated individuals during the Alpha (B.1.1.7) and Delta (B.1.617.2) waves. However, data on the efficacy and safety of tixagevimab/cilgavimab in vaccinated solid organ transplant recipients during the Omicron wave is limited. To address this, we conducted a retrospective cohort study comparing 222 solid organ transplant recipients (SOTRs) who received tixagevimab/cilgavimab for pre-exposure prophylaxis and 222 vaccine-matched solid organ transplant recipients who did not receive tixagevimab/cilgavimab. Breakthrough SARS-CoV-2 infections occurred in 11 (5%) of SOTRs who received tixagevimab/cilgavimab and in 32 (14%) of SOTRs in the control group (p .001). In the tixagevimab/cilgavimab group, SOTRs who received the 150-150 mg dose had a higher incidence of breakthrough infections compared to those who received the 300-300 mg dose (p = .025). Adverse events were uncommon, occurring in 4% of our cohort and most were mild. There was no significant change in serum creatinine or liver chemistries in kidney and liver transplant recipients, respectively. In conclusion, we found that tixagevimab/cilgavimab use is safe and associated with a lower risk of breakthrough SARS-CoV-2 infection in vaccinated solid organ transplant recipients during the Omicron wave.

Antibody-mediated rejection is a major cause of long-term graft loss in kidney transplant patients. T follicular helper (Tfh) cells are crucial for assisting B cell differentiation and are required for an efficient antibody response. Anti-thymocyte globulin (ATG) is a widely used lymphocyte-depleting induction therapy. However, little is known about how ATG affects Tfh cell development and donor-specific antibody (DSA) formation. We observed an increase in circulating Tfh cells at 6 months after kidney transplant in patients who received ATG. Using an NP-OVA immunization model, we found that ATG-treated mice had a higher percentage of Tfh cells, germinal center B cells, and higher titers of antigen-specific antibodies compared to controls. ATG-treated animals had lower levels of IL-2, a known Bcl-6 repressor, but higher levels of IL-21, pSTAT3 and Bcl-6, favoring Tfh differentiation. In a mouse kidney transplant model, ATG-treated recipients showed an increase in Tfh cells, DSA and C4d staining in the allograft. Although ATG was effective in depleting T cells, it favored the expansion of Tfh cells following depletion. Concomitant use of IL-2, tacrolimus, or rapamycin with ATG was essential to control Tfh cell expansion. In summary, ATG depletion favors Tfh expansion, enhancing antibody-mediated response.

BackgroundAvailable SARS-CoV-2 vaccines have reduced efficacy against the Omicron variant in immunocompetent individuals. Kidney transplant recipients (KTRs) have diminished antiviral responses to wild-type SARS-CoV-2 after vaccination, and data on antiviral responses to SARS-CoV-2 variants, including the Omicron variant, are limited.MethodsWe conducted a prospective, multi-center cohort study of 51 adult KTRs who received three doses of BNT162b2 or mRNA-1273. Blood and urine samples were collected before and four weeks after the third vaccine dose. The primary outcome was anti-viral antibody responses against wild-type and variants of SARS-CoV-2. Secondary objectives included occurrence of breakthrough SARS-CoV-2 infection and non-invasive monitoring for rejection using serum creatinine, proteinuria, donor-derived cell-free DNA and donor-specific antibodies. Sera from pre-pandemic healthy controls and KTRs were used for comparison.Results67% of KTRs developed anti-wild-type spike antibodies after the third vaccine dose, similar to the Alpha (51%) and Beta (53%) variants, but higher than the Gamma (39%) and Delta (25%) variants. No KTRs had neutralizing responses to the Omicron variant before the third vaccine dose. After the third dose, fewer KTRs had neutralizing responses to the Omicron variant (12%) compared to wild-type (61%) and Delta (59%) variants. Three patients (6%) developed breakthrough SARS-CoV-2 infection at a median of 89 days. No KTRs developed allograft injury, de novo donor-specific antibodies or allograft rejection.ConclusionIn KTRs, a third dose of mRNA vaccines increases antibody responses against wild-type and variants of SARS-CoV-2, while neutralizing responses to the Omicron variant remain markedly reduced.

Pulmonary mucormycosis is a rare opportunistic invasive fungal infection that disproportionately affects immunocompromised hosts and carries high morbidity and mortality. It is traditionally treated with combined pharmacologic and surgical modalities. Here we present a case of pulmonary mucormycosis in a patient whose disease burden precluded surgical management, and in whom acute kidney injury necessitated therapy with an alternative to the recommended pharmacologic antifungal therapy. Keywords: Mucormycosis, Pulmonary, Infections, Isavuconazole

ObjectiveQatar is a small country on the Eastern coast of the Arabian Peninsula. Its population is a unique mixture of native citizens and immigrants. We aimed to describe the features of epilepsy in Qatar as such information is virtually lacking from the current literature.MethodsWe summarized information retrospectively collected from 468 patients with epilepsy seen through the national health system adult neurology clinic.ResultsEpilepsy was classified as focal in 65.5% of the cases and generalized in 23%. Common causes of epilepsy were as follows: stroke (9%), hippocampal sclerosis (7%), infections (6%), and trauma (6%). Sixty-six percent of patients were receiving a single antiepileptic drug, with levetiracetam being the most frequently prescribed drug (41% of subjects). When the patients were divided by geographical background, remote infections caused the epilepsy in 15% of Asian patients (with neurocysticercosis accounting for 10%) but only in 1% of Qatari and 3% of Middle East/North African subjects (with no reported neurocysticercosis) (p

Epstein-Barr virus (EBV) is implicated in the tumorigenesis of a variety of malignancies, including Burkitt’s lymphoma, Hodgkin’s disease and nasopharyngeal carcinoma (NPC). EBV+ lymphoepithelioma-like cholangiocarcinoma (LELCC) is a rare type of intrahepatic cholangiocarcinoma with a distinct pathology and poorly understood treatment options. Morphologically, this neoplasm resembles undifferentiated NPC, a commonly EBV+ tumour with a prominent lymphoid infiltrate. Almost all of the current literature regarding LELCC describes early stage tumours that are treated surgically and achieve good outcomes. In contrast, this report documents a late stage LELCC treated unsuccessfully with systemic chemotherapy.

RationaleEpilepsy is one of the most prevalent neurologic conditions. It is estimated to affect 70 million people worldwide. Epilepsy is an important cause of disability and mortality. It is associated with social stigma and significant economic costs. Although epilepsy is a disease with a worldwide distribution, its prevalence varies between different countries. Very little is known about the epidemiology of epilepsy in Qatar. Qatar's population is a mixture of native citizens and immigrants. We aim at describing the features of epilepsy in Qatar as such information is virtually lacking from the current literature.MethodsA database was created in 2014 to summarize information retrospectively collected on patients with epilepsy seen through the national health system (HMC) adult neurology clinic. For each subject, in addition to the typical demographic variables, we identified the age at onset, seizure types, epilepsy syndrome, etiology, treatment and outcome. Brain imaging and EEG results were also tabulated. All these variables were analyzed using the statistical package for social science (IBM-SPSS, version 20).ResultsOf 504 patients included in the database, 467 with sufficient information were analyzed. Sixty percent were men. The mean age at the last clinic visit was 35. Native Qataris represented 38.5%, Asian subjects 33%, and Middle Eastern/North African (MENA) origin accounted for 25% of the studied population. Generalized tonic-clonic seizures were the most common seizure type, noted in 89% of subjects. Epilepsy was classified as focal in 65.5% of the cases, and generalized in 23%. EEGs were abnormal in 55.5 %, showing epileptiform discharges in 49% of subjects. Imaging studies revealed epileptogenic pathologies in 40% of reports. Common causes of epilepsy were: vascular (11%), hippocampal sclerosis (8%), infectious (6%) and trauma (6%). Sixty six percent of patients were receiving a single antiepileptic drug, and 53% were seizure free at the last follow-up. Overall, the most commonly prescribed drug was Leviteracetam (41%) followed by Valproic Acid (25%) and Carbamazepine (22%). On current therapy, 54% of patients were seizure-free, 41% had a partial response and five percent were refractory. When the patients were divided by geographical background, some differences were noted. Remote infections caused the epilepsy in 15% of Asian patients (with neurocysticercosis accounting for 10%), but only in 1% of Qatari and 3% of MENA subjects (with no reported neurocysticercosis) (p

An efficient method to generate cardiac tissue from other tissues has great therapeutic potential for patients suffering from cardiovascular disease. Pluripotent stem cells, such as embryonic stem (ES) cells, and so-called induced pluripotent stem (iPS) cells can be differentiated into multiple cell types, including cardiac myocytes. However, therapeutic use of these cells has several important risks, including cancer as well as loss of differentiated cell identity and function or "drift." Transdifferentiation, the generation of cell types from other differentiated cell types, is an attractive alternative because it poses little risk of cancer and may give rise to cells whose identity is locked in. However, the direct reprogramming of adult fibroblasts into cardiac myocytes is inefficient and the transcription factors that drive this process are unknown. To circumvent these hurdles we hypothesized that fetal derived cells may be more amenable to reprogramming into cardiac myocytes with defined transcription factors. To this end, fetal derived fibroblasts and mesenchymal cells were transduced with transcription factors that have been shown to play a role in myocyte specification and maintenance, including GATA4, Mef2c, Tbx5 and Nkx2.5. To test this hypothesis, the transcription factors were cloned into lentiviral vectors, which were used to infect fibroblasts and mesenchymal cells. Infected cells were then cultured in different media. To assess the efficiency of the reprogramming, RNA was extracted from infected and uninfected cells, and quantitative RT-PCR was used to evaluate the expression levels of the transcription factors and known cardiac genes. We expected to observe higher levels of the transcription factors and cardiac markers in the infected cells relative to the uninfected cells. The results showed that the infected cells expressed higher levels of the transcription factors and a few cardiac markers relative to the uninfected cells. However, due to the small increase in the levels of only a few cardiac markers, the reprogramming was concluded to be inefficient. To make the reprogramming more efficient, other as yet unrecognized transcription factors possibly in the GATA family of transcription factors and culture conditions are currently being considered.